Personalized Immunotherapy for Tumor Diseases and Beyond E-Book
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- Herausgeber: Bentham Science Publishers
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This book introduces personalized immunotherapy with multi-dimensional models of analysis to determine the best plan for immunotherapy of patients. The book introduces readers to some basic concepts which lay the foundation for personalized immunotherapy: the development of a major histocompatibility complex (MHC), the genome profile of T cells and tumor cells, and genome-wide association studies. Chapters also cover special topics such as new immunoassay methods related to personalized immunotherapy and targeted immunotherapy which are geared towards familiarizing readers with current research practices. Focusing on the central theme of personalized immunotherapy, the authors provide a wealth of information about T-cell screening, tumor neoantigen cloning, primary tumor cell culture for T-cell cloning, bioinformatics strategies for understanding T-cell and primary tumor cell biology and function, and new developments in research on adoptive T-cell immunotherapy. These developments include T-cell gene therapy and T-cell gene editing, transgenic T-cells for increasing affinity to tumor cells such as CAR T-cells and TCR T-cells, and the systematic modeling of polyclonal specific T-cells and biobank technology. Key Features:- Introduces readers to basic concepts in personalized medicine and immunotherapy- Presents current information about immunological assays used in research- Presents an overview of T cell immunotherapy and cloning techniques- Presents an overview of tumor cell bioinformatics and its role in immunotherapy- Includes new developments and references for personalized immunotherapy techniques (T-cell gene therapy and T-cell gene editing, transgenic T-cells which target CAR T-cells and TCR T-cells, and polyclonal T-cell modeling) - Includes a section on biobanking- Presents information in an easy-to-read format for a wide range of readers- Brings contributions from experts with over 30 years of experience in personalized immunotherapy Personalized Immunotherapy for Tumor Diseases and Beyond is an ideal handbook for medical professionals and students involved in personalized medicine, immunology and oncology. General readers interested in the new developments in these fields will also benefit from the information provided.
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Seitenzahl: 464
Veröffentlichungsjahr: 2020
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PREFACE
T-cell adoptive immunotherapy for tumor diseases has been studied for nearly three decades. Steven Rosenberg was a pioneer in the successful use of tumor-infiltrating lymphocytes (TIL) in treating tumor diseases. In 1986, he first discovered that TIL could recognize autologous tumor cells. In 1988, he successfully applied autologous TIL to metastatic melanoma. Since 1989, we have used T-cell adoptive immunotherapy to treat more than 200 cases and published more than 50 papers. T-cell adoptive immunotherapy, along with its newer generation techniques, can be increasingly used to treat various solid tumor diseases such as ovarian, brain, lung, and liver cancers. Before introducing the preface, I will first review T-cell adoptive immunotherapy in three stages to summarize the thirty-year development of T-cell adoptive immunotherapy: (I) the early stages of T-cell adoptive immunotherapy such as TIL adoptive immunotherapy; (II) research and development (R& D) of a new generation of T-cell adoptive immunotherapy; and (III) clinical trials of the next-generation T-cell adoptive immunotherapy.
Early period R& D of T-cell adoptive immunotherapy:
After 1987, Dr. Rosenberg discovered that TILs could be cultured with the aid of the cytokine IL-2 and induced TIL exhibited cytotoxic activity against melanoma cells in vitro. TILs isolated from tumor samples were the earliest trials of ACT conducted at the surgical branch of the National Cancer Institute (NCI) in 1988. At the time, objective responses were observed in patients with metastatic melanoma. For the optimal procedure of TIL isolation and proliferation, we carefully studied the NCI protocol and then modified the protocol to establish a new TIL culture and proliferation procedure. Our earliest findings showed that the modified procedures are different from the NCI conventional approaches: (1) enzyme digestion of tumor tissue can result in loss of the signaling of T-cell so that only collagenase IV digestion can keep signaling intactness of T-cell and (2) adding process with a cleaning inhibiting factors and inhibiting cells will increase TIL activity and cytotoxicity to tumors, now the inhibiting factors, inhibiting cells and tissue called as tumor microenvironment (TME) after thirty years. After establishing the modified method, we also routinely employ TIL measurement by the proliferation and cytotoxicity assay since TIL efficacy is variable from a solid tumor. Although TILs effectively used for solid tumor have been debated more than 30 years, a few laboratories have reported that TILs have also been successfully applied to different solid tumors, such as pancreatic cancer, head, and neck cancer, lung cancer, brain cancer and liver cancer under the optimal culture procedures and right therapeutic conditions.
In the early phase of T-cell adoptive immunotherapy, three major breakthroughs were developed to increase TIL efficacy: (I) cytokines induction with IL-2 and IL-12; IL-2 and Anti-CD3 and IL-2 and Anti-CD3/CD28 for their cultures; (II) clinical TIL application combined with chemotherapy or lymphodepletion prior to adoptive cell therapy (ACT); (III) development of TIL location administration. These developments demonstrated the significant benefits in the early TIL clinical application (selected publications from our work as below).
R&D of a new generation of T-cell adoptive immunotherapy: With the maturation of gene transfer technology, three areas developed rapidly:
the affinity of T cells to tumor cells, such as (I) TCR T-cells (T-cell receptor engineered T-cell) and CAR T-cells (chimeric antigen receptor T-cell) related to the reconstructs of the signal structure of TCR molecules; (II) T-cell editing technology; (III) polyclonal TIL combined with a single T-cell genome linking new compounds to improve the efficacy of personalized immunotherapy. TCR T-cells and CAR T-cells on T-cell adoptive immunology have been studied for more than 30 years. Chimeric TCR that achieves T-cell specific affinity was first reported in 1989 by cloning anti-TNP mRNA into TCR V and C chain targeting cells. Since 1989, we had also tried DHBsAb (Duck Hepatitis B virus surface antibody) from duck to clone into human CD3 in TIL to form DHBsAb-CD3 CAR-T cells to treat hepatocellular carcinoma under the guidance of Dr. Shen (Picture A), who was my mentor when I was a graduate MD student thirty-five years ago). That time, DHBsAb-CD3 chimeric TIL failed to treat DHBV and HBV HCC cells due to limited knowledge of the early CD3 and TCR structures. Later, Irving and Weiss discovered that CD8 and CD3ζ chains could independently mediate T-cell activation of endogenous TCR; thus, CARs can be reconstructed as an extracellular domain for tumor antigen recognition as well as multiple intracellular signaling domains that mediate T-cell activation. Currently, third-generation chimeric receptors with CD28/4-1BB/CD3ζ can be used to treat chronic lymphocytic leukemia (CLL) with clinical significance. After decoding the TCR signaling protein, we have found that TCRs rely on the patient's human leukocyte antigen (HLA) allele, allowing for class I peptide-MHC binding, and ultimately cancer cell destruction. At present, TCR T-cells are successfully used in solid tumors. Molecular screening techniques of shared or specific tumor antigen/peptides play an essential role in personalized T-cell immunotherapy. We had initiated a phage-display screening system for specific peptides on malignant myeloid cells under the support of Drs. HD. Preisler and G Smiths in 1996 (Picture B). After more than 20 years of work, we have set up single-cell techniques, either supporting the specific targeting screening or a new generation T-cell adoptive immunotherapy based on single T-cell genomic profiles. The personalized immunotherapy based on genomics and GWAS from individual T-cell genomic profiles linking to a network and then further linking to the new compounds can be safely and effectively applied to personalized immunotherapy for different patients (selected publications from our work as below).
Clinical trials of the new generation of T-cell adoptive immunotherapy:
Since CAR T-cells have been proven to be effective in treating B-cell hematological malignancies, there are now more than 300 clinical trials on treating hematological malignancies through CAR T-cells. TCR T-cells have been increasingly reported for the treatment of solid tumors. Also, the medical industry is also advancing research on different stages of CAR T-cells and TCR T-cells for various tumor diseases (selected publications as below).
After nearly 30 years of developing T-cell adoptive immunotherapy as summarized above, our book will focus on personalized immunotherapy, a new strategy for cancer treatment in the 21st century. Personalized immunotherapy will involve a set of biochemical, immune, and genomic characterization of the tumors using multi-dimensional analyses in order to lead to an optimal decision on the appropriate immune treatment. Therefore, this book on personalized immunotherapy will first introduce some foundational concepts: MHC research and development, the genomic profiles and genome-wide association study (GWAS) of T-cells and tumor cells from patients, and technologies which provide the basis of personalized immunotherapy. The knowledge has led to the rapid development of personalized immunotherapy in the past decades.
Because recent research in personalized immunotherapy involves targeting therapy, in the book, we will introduce some new immunoassay methods related to personalized immunotherapy. Subsequently, we will present targeting immunotherapy in two chapters: personalized immunotherapies that depend on the tumor immune microenvironment (TIME) (such as PD1 or PDL1-related checkpoint targeted therapy) and immunotherapy dependent on the tumor microenvironment (TME) including IDO (indoleamine 2,3-dioxygenase) inhibitors and ADO (CD39/CD73/adenosine) inhibitors.
The central portion of this book, consisting of eight chapters, is related to personalized T-cell immunotherapy, which includes the basics of personalized T-cell immunotherapy and the essentials of the latest developments in personalized T-cell immunotherapy. The former with three chapters consists of new molecular technologies such as T-cell screening and cloning of tumor neoantigens, a new generation of primary tumor cell culture for T-cell cloning, bioinformatics platform of T-cells and primary tumor cells. The latter or personalized T-cell adoptive immunotherapy with four chapters will present the development and future of adoptive T-cell immunotherapy; the development of T-cell gene therapy and T-cell genome editing; the affinity of transgenic T-cells to tumor cells such as CAR T-cells and TCR T-cells; and systematic modeling of polyclonal specific T-cells. Finally, we will present a biobank for personalized immunotherapy, which we have been studying for more than twenty years.
Personalized immunotherapy is a new immunotherapy model for studying individualized cancer therapy, which involves "providing the right immunotherapy for the right people at the right time." Due to the complexity of individual tumors and immune responses, traditional immunotherapy models have faced challenges. To address this, we have written the book on updated strategies for cancer immunotherapy.
Selected publications for our early period of T-cell adoptive immunotherapy
REFERENCES
[1]Li B. Shanqing Dong, Xiheng Zheng, Yumin Zu, Baoyu Wu and Deyuan Lu. A New Experimental and Clinical Approach of Combining Usage of Highly Active Tumor-infiltrating Lymphocytes and Highly Antitumor Drugs for the Advanced Malignant Tumor. Chinese Medical Journal 1994; 107(11): 803-7.[PMID: 7867384][2]Li B, Shen D. Preliminary Study on the Resting Status of Tumor-infiltrating Lymphocytes. Chinese Microbiology and Immunology 1994; 14(6): 399-402.[3]Li Biaoru. Tong Shanqing; Hu Baoyu; Zhu Youming; Zhang Xiheng; Wu Jianhe; Lu Deyuan; Lu Jing; Study on the effect of enzymatic digestion on the activity of tumor infiltrating lymphocytes; Journal of Molecular Cell Biology 1994 01[4]Li B. Tong Shanqing; Zhang Xiheng; Zhu Youming; Hu Baoyu; Lu Deyuan; Lu Jing; Gu Qinlong; Research on TIL proliferation, phenotype and lethality of human malignant solid tumors 199405.[5]Li Biaoru. Tong Shanqing; Zhu Youming; Hu Baoyu; Zhang Xiheng; Lu Jing; Wu Jianhe; Hu Hongliang; Shen Dinghong; Lu Deyuan; Establishment of a method for separation of tumor infiltrating lymphocytes with high vitality; Journal of Immunology 1994 01[6]Zhu Y, Zhang X. Biaoru Li; Hu Baoyu; Wu Jianhe; Tong Shanqing; Removal of tumor-doped tumor cells in tumor infiltrating lymphocyte culture; Journal of Shanghai Jiaotong University 199502.[7]Jian Tao, Zhang Guochi, Ding Jianqing, Zhang Xiheng. 7. Tao Jian, Zhang Guochi, Ding Jianqing, Zhang Xiheng, Biaoru Li, Tong Shanqing, Experimental study of receptor-mediated TNFα gene transfer, Journal of Shanghai Second Medical University, 2000, Vol.20, No.01.[8]Li Biaoru. Xu Wei, Qian Guanxiang, Zhang Xiheng, Dong Shanqing, Chen Shishu, Methodology of TNF gene transduction of tumor infiltrating lymphocytes, Journal of Shanghai Second Medical University, 1995, Vol. 15 No. 3,[9]Ding Jianqing, Qian Guanxiang. Xu Wei; Zhu Youming; Hu Liang; Hu Baoyu; Zhang Tengfei; Zhang Xiheng; Xu Rongting; Tong Shanqing; Xu Weizhen; Lu Deyuan; Chen Shishu; A preliminary study of tumor necrosis factor gene transduction of tumor infiltrating lymphocytes Application; Chinese Journal of Cancer Biotherapy 1995 01,[10]Wang JH, Tong SQ. Biaoru Li, Ding JQ, Hu BY, Zhu YM, Lu DY, Hua ZD, Lu J. Immunological Character of TIL in Ovarian Carcinoma. Chin J Cancer Res 2000; 12(2): 99-104.[http://dx.doi.org/10.1007/BF02983432][11]Gu Qinlong. 11. Gu Qinlong, Biaoru Li, Electron microscopic observation of human gastric cancer TIL cells in vitro killing MKN45 gastric cancer cell lines, Journal of Shanghai Second Medical University, 1995, Vol. 15 No. 4.[12]Gu Qinlong, Lin Yanqi, Yin Haoran. Zhu Youming, Hu Baoyu; Phenotype and cytotoxic activity of infiltrating lymphocytes in gastrointestinal tumors[J] Journal of Shanghai Second Medical University;1996-03.[13]Gu Qinlong, Lin Yanqi, Yin Haoran. Biaoru Li, Zhu Youming, Hu Baoyu; Preliminary study on cryopreservation of tumor infiltrating lymphocytes. Journal of Immunology, 1995-04[14]Deng Y, Gu Q. Biaoru Li; Zhang Xiheng; MTT colorimetric assay for LAK and TIL cell activity in cord blood; Journal of Shanghai Jiaotong University 199502.[15]Hu Bingcheng, Li Guowen, Wei Cheng, Shen Jiankang, Dong Lin. Biaoru Li, Clinical application of infiltrating lymphocytes in malignant brain tumors, Journal of Immunology, 1997-02[16]Hua Zude, Jing Lu, Li Huifang. Zhu Youming; Tong Qingshan; Clinical study of tumor infiltrating lymphocytes in ovarian cancer. Chinese Journal of Obstetrics and Gynecology 1996 09[17]Li H, Jing L, Hua Z. Biaoru Li; Tong Shanqing; Lu Deyuan; Study on the killing activity of TIL cells in ovarian cancer 199505.[18]Jing Lu. Hua Zude; Zhu Youming; Tong Shanqing; Research on TIL yield and vitality of different materials; Journal of Immunology 1995 03[19]Jing Lu, Hu Liewei, Hua Zude. Biaoru Li, Tong Shanqing; Analysis of the therapeutic effects of different therapeutic approaches for TIL; 1996-02[20]Jing L, Hua Z, Li H. Biaoru Li, Zhu Youming, Tong Shanqing; In vitro study of ovarian cancer TIL J199506.[21]Jing L, Duan LD, Hua Z. Biaoru Li, Zhu Youming; Tong Shanqing; Preliminary observation of biological characteristics of cord blood lymphocytes, Journal of Shanghai Jiaotong University 199501.[22]Tong Shanqing, Wang Jianhua. Ding Jianqing; Hu Baoyu; Zhu Youming; Lu Deyuan; Hua Zude; Lu Jing; Biological characteristics of invasive lymphocytes from ovarian cancer; Chinese Journal of Immunology 2000 03[23]Cai Xiaomin, Jing Lu, Hua Zude. Tong Shanqing; Clinical Application of TIL from Different Sources; Journal of Immunology 1996 04[24]Tong S, Wang J. Biaoru Li, Ding Jianqing; Hu Baoyu; Zhu Youming; Lu Deyuan; Hua Zude; Lu Jing; Biological characteristics of invasive lymphocytes from ovarian cancer. Chin J Immunol 2000.INTRODUCTION
After nearly 30 years of developing T-cell adoptive immunotherapy as summarized above, our book will focus on personalized immunotherapy, a new strategy for cancer treatment in the 21st century. Personalized immunotherapy will involve a set of biochemical, immune, and genomic characterization of the tumors using multi-dimensional analyses in order to lead to an optimal decision on the appropriate immune treatment. Therefore, this book on personalized immunotherapy will first introduce some foundational concepts: MHC research and development, the genomic profiles and genome-wide association study (GWAS) of T-cells and tumor cells from patients, and technologies which provide the basis of personalized immunotherapy. The knowledge has led to the rapid development of personalized immunotherapy in the past decades.
Because recent research in personalized immunotherapy involves targeting therapy, in the book, we will introduce some new immunoassay methods related to personalized immunotherapy. Subsequently, we will present targeting immunotherapy in two chapters: personalized immunotherapies that depend on the tumor immune microenvironment (TIME) (such as PD1 or PDL1-related checkpoint targeted therapy) and immunotherapy dependent on the tumor microenvironment (TME) including IDO (indoleamine 2,3-dioxygenase) inhibitors and ADO (CD39/CD73/adenosine) inhibitors.
The central portion of this book, consisting of eight chapters, is related to personalized T-cell immunotherapy, which includes the basics of personalized T-cell immunotherapy and the essentials of the latest developments in personalized T-cell immunotherapy. The former with three chapters consists of new molecular technologies such as T-cell screening and cloning of tumor neoantigens, a new generation of primary tumor cell culture for T-cell cloning, bioinformatics platform of T-cells and primary tumor cells. The latter or personalized T-cell adoptive immunotherapy with four chapters will present the development and future of adoptive T-cell immunotherapy; the development of T-cell gene therapy and T-cell genome editing; the affinity of transgenic T-cells to tumor cells such as CAR T-cells and TCR T-cells; and systematic modeling of polyclonal specific T-cells. Finally, we will present a biobank for personalized immunotherapy, which we have been studying for more than twenty years.
Personalized immunotherapy is a new immunotherapy model for studying individualized cancer therapy, which involves "providing the right immunotherapy for the right people at the right time." Due to the complexity of individual tumors and immune responses, traditional immunotherapy models have faced challenges. To address this, we have written the book on updated strategies for cancer immunotherapy.
List of Contributors
MHC and Cancer Immunotherapy
Li-Hua Jiang1,*,Wei-Hua Yan2Abstract
Major Histocompatibility Complex (MHC) is a gene region, which is named human leucocyte antigen (HLA) in humans. The human leukocyte antigen (HLA) system is a highly polymorphic family of genes involved in immunity and responsible for identifying self-cells versus no self-cells. Although HLA typing is essential for solid organ and bone marrow transplantation, at present, MHC is going to study on cancer immunotherapy increasingly. In order to introduce MHC related to cancer immunotherapy, the chapter aims at focusing on several MHC issues related to cancer immunotherapy. For example, MHC research and development (R&D) in MHC class I molecular loss related to cancer immunotherapy; tumor immune escape related to nonclassical MHC I; T-cell epitope vaccines; as well as MHC issues in adoptive immune cell therapy and personalized immunotherapy. In each part for MHC related to immune responses for tumor disease, we also introduce clinical uses in a study on MHC issues for T-cell immunotherapy, MHC for T-cell vaccines, and MHC TCR reconstructions for tumor shared/specific antigen related TCR T-cell personalized immunotherapy.
OVERVIEW OF MHC GENES AND MOLECULES
The major histocompatibility complex (MHC) is a common genetic region in vertebrates. It is called human leukocyte antigen (HLA) in humans and histocompatibility-2 (H2) in mice. MHC contains multiple genetic loci, which is highly polymorphic. It was first discovered because it played a decisive role in determining transplant rejection, that is, the degree of histocompatibility between the donor and recipient of organ tissue transplantation [1].
It was later uncovered that its main biological role of MHC class I and II molecule-encodes provide antigens that can be recognized by T lymphocytes [2], which are the center of the T cell immune response. Another interesting issue is that MHC class I molecules (including classical and nonclassical Class I molecules) can be used as targets for surface inhibitory receptor recognition by NK, playing an essential role in regulating immune cells' effect for tumor immunotherapy [3].
1. Characteristics of the HLA Gene Complex
The classical HLA gene system is located in the short arm of chromosome 6 (the 6p21 region) and has a length of 3600 kb as Fig. (1). It contains 224 gene loci, of which 128 are functional genes with product expression [4].
Fig. (1)) HLA gene complex.The most important loci are the classical HLA class I, containing HLA-A, HLA-B and HLA-C genes encoding the classical HLA class I molecules alpha chains; and the classical HLA class II encoding the alpha and beta chains from genes of HLA-DRA, HLA-DRB, HLA-DQA, HLA-DQB, HLA-DPA, HLA-DPB genes. Molecules encoded by HLA-E, HLA-F, HLA-G, and MIC loci, which are located in nonclassical HLA class I loci, play an important role in immune regulation. Other genes are also involved in the body's immunity, such as HLA-DM, HLA-DO, TAP, and PSMB for re-antigen processing and presentation, complement genes, and TNF genes for inflammation.
Most of these genes have polymorphism or be highly polymorphic at each locus with a difference of one base to multiple base pairs, individually, so that clinically HLA polymorphisms have become a major obstacle to allografts, and often also become necessary factors to in immunotherapy of tumors [5].
2. HLA Molecule Structure
The classical HLA class I molecules alpha chain encoded from HLA-A, HLA-B, and HLA-C and β2 micro-globulin (β2M) encoded by the non-HLA gene from chromosome 15 as Fig. (2). Classical HLA class II molecules composed of the alpha chain encoded by the A gene of HLA class II and the beta chain encoded by the B gene, encoding from HLA-DR, HLA-DQ, and HLA-DP as Fig. (2).
Fig. (2)) HLA structure.The critical difference between Class I molecules and Class II molecules is that the two ends of the peptide-binding groove are closed in Class I molecules so that Class I molecules generally can only accommodate peptides of 9 amino acids. In contrast, Class II molecules are open so that they can accommodate more peptides. For example, the peptide with a length of 16-18 amino acids with nine amino acids are bound in the groove [7]. The Ig-like region is responsible for maintaining the stability of the three-dimensional structure and selectively binds to CD4 or CD8 molecules on the surface of T-cells, thereby limiting the recognition pattern of T-cells. CD8+T-cells recognize antigens presented by MHC class I molecules, while CD4+T-cells recognize the antigen presented by MHC class II molecules.
3. Distribution and Function of HLA Molecules
Classical HLA class-I molecules are distributed on the surface of all nucleated cells, responsible for presenting the antigens produced inside the cells for recognition by CD8+T-cells. In contrast, HLA class II molecules are mainly distributed in antigen-presenting cells (APC), responsible for presenting antigens for recognition by CD4+T-cells.
The presentation of MHC molecules to antigens is a prerequisite for immune recognition of T-cells because the TCR antigen receptor only recognizes the linear epitope (epitope) presented by MHC, affinity short peptide cut off from the protein antigen. Therefore, the recognition of antigens by T-cells is deeply affected by MHC molecules, so-called MHC restriction [8].
MHC class I molecules also have an important function as ligands for some receptors on the surface of NK cells, including KIR2D/KIR3D belonging to the killer cell immunoglobulin-like receptor (KIR) family, killer cell lectin-like receptor (KLR), CD94/NKG2 family, regulating the killing activity of NK cells. The MHC class I molecules play a decisive role in the inhibitory receptors of NK cells because NK cells can recognize and kill tumor cells that lack own MHC class I molecules [3].
4. MHC Allele Detection
The typing of HLA based on the antigenic difference of HLA molecules is to use allotype antisera with complement-dependent micro-lymphocytic methods. Following research and development (R&D) of molecular biology techniques, the molecular typing method has, currently, replaced the serological method. According to the purposes of different laboratories, the technologies currently used are:
PCR-SSO (Sequence-specific oligonucleotide probes) can use PCR to amplify specific fragments of the HLA gene, fix the PCR amplification product on the hybrid membrane, and then use a series of labeled oligonucleotide oligo-nucleotide probes for hybridizing various HLA allele-specific DNA sequences, and finally, determine the type of allele according to the hybridization pattern of each specimen.PCR-SSP (Sequence-specific primer assay), based on the DNA sequence differences of various HLA alleles, applies for a series of targeted primers to amplify various allele-specific fragments, and then to determine the HLA allele by electrophoresis based on PCR products.Real-time PCR: the basic principle is like PCR-SSP, but it is more convenient and accurate because it does not require electrophoresis operations after PCR. After the first half of the method is the same as PCR-SSO; the PCR products are identified by Sanger sequencing for alleles.Next-generation sequencing (NGS): After RNA-seq and DNA-seq are developed since 1995, most scientists working on screening techniques have often used genomic techniques to discover new candidates of neoantigens related to TCR recognizing MHC-peptide. Moreover, engineering T-cells with tumor antigen-specific TCR related to binding MHC can be used to generate TCR T-cells for personalized adoptive T-cell immunotherapy.MHC CLASS I MOLECULAR LOSS AND CANCER IMMUNOTHERAPY
A variety of biological products have been used for cancer immunotherapy such as BCG, Polysaccharide K (PSK), IL-2, IFN, tumor vaccine, tumor infiltration lymphocytes (TIL). In recent years, novel therapies using antibodies that block immune checkpoint molecules involved in the regulation of T-cell has achieved good results. Unfortunately, only small proportions of patients benefit from these therapies [9]. These immune escaping indicated T-cells in tumor immune surveillance/escape, tumor occurrence and resistance to immunotherapy, for example, loss of tumor antigen, lack of co-stimulatory signals for T cell activation, the resistance of tumor cells to IFN, Resistance of tumor cells to apoptosis, immune negative regulatory cells and immunosuppressive factors in the tumor microenvironment (TME). Considering that the presentation of tumor antigen by MHC I is the premise of T cell immune recognition, the lack or down-regulation of MHC I expression on the tumor cell surface is an important strategy for immune escapes.
1. Loss of Class I HLA Expression in Tumor Tissues
Class I HLA molecules are normally expressed in nearly all nucleated cells, except for trophoblastic placental cells, central nervous system, and an exocrine portion of the pancreas. Hepatocytes and skeletal muscle cells have relatively low expression of Class I HLA proteins. Due to the characteristic of co-dominant expression for Class I HLA alleles, each cell can express six different molecules, including two types of A, B, and C, respectively. All the HLA molecules are thought to be expressed in tumor cells at the early stage of tumorigenesis. However, studies have shown that loss of Class I HLA expression on the tumor cell surface is very common in various types of tumor [10], such as biliary tract carcinoma, bladder carcinoma, breast carcinoma, cervical carcinoma, colorectal carcinoma, endometrial cancer, esophageal carcinoma, gastric carcinoma, glioblastoma, head and neck carcinoma, hepatocellular carcinoma, lymphoma and leukemia, lung carcinoma, melanoma, neuroblastoma, ovarian cancer, pancreas carcinoma, prostate carcinoma, renal cell carcinoma, thyroid carcinoma, and uveal melanoma. The detection rate is estimated to be around 90% in many neoplasms [11].
2. Types of Class I HLA Deletion.
Various types of Class I HLA deletion exist in tumor tissues [11, 12]. Compared with complete deletion, the partial deletion of Class I HLA is found to have higher carcinogenicity. This is because the part of a class I HLA with high efficiency for presenting tumor antigen epitopes is lost, resulting in the failure of T cells to recognize tumor antigen efficiently.
Complete deletion of Class I HLA molecules. The mechanisms of formation include β2M deletion caused by loss of heterozygosity (LOH) on chromosome 15 and mutation of β2M gene on another chromosome 15, transcriptional down-regulation of antigen presentation machinery (APM), HLA-I or β2M genes, and hypermethylation of Class I HLA genes [11-16].Deletion of haplotypes of HLA. Deletions occur as a set of HLA genes (type A, B, or C), which may be involved in the loss of an entire or part of chromosome 6 [11].Down-regulated expression of HLA gene locus (type A, B, or C). As a result, tumor cells only express the other two gene loci of the four alleles, which can be caused by either decreased transcription level or expression of specific transcription factors. Cytokines secreted by TH1 cells, such as IFN-γ, can reverse the down-regulated expression [11, 12].Deletion of HLA alleles. The deletion occurs at any 1 product from the 3 class I HLA gene loci of the six alleles, which may be caused by somatic mutation of the allele. It is undetectable in most cases since a specific monoclonal antibody against that allele product is required for the detection [11, 12].Co-occurrence of above-mentioned II, III and IV. This type of deletion may lead to the expression of 1 allele to the minimum [15-17].Unresponsive deletion to up-regulation of Class I HLA induced by IFN. This type may be caused by genetic mutations on molecules related to IFN-γ or IFN-α signal pathway [18, 19].In summary, loss of Class I HLA expression can be caused through a variety of mechanisms, including abnormalities occurring at any step during synthesis and assembly of Class I HLA molecules. According to whether the deletion can be reversed through interacting with cytokines produced by immunotherapy, the mechanisms are divided into 2 classes [11, 20, 21]: Irreversible: including LOH, mutations or deletions on chromosome 6 and 15 (harboring α chain gene and β2M gene, respectively), defect of IFN signal transduction pathway (such as interruption of Jak-STAT pathway); Reversible: including down-regulated expression of HLA-A, B or C gene locus, heavy chain gene of Class I, β2M gene, APM genes resulting from abnormal transcription regulation, down-regulation of Class I or APM gene expression caused by hypermethylation, and inhibition upon post-transcriptional modification of Class I MHC mRNAs.
3. Expression of Class I HLA Molecules and Efficiency of Immunotherapy
Several scenarios are raised to predict the immunotherapy efficacy on class-I HLA expression. As for tumors with positive expression of Class I HLA molecules, the immunotherapy efficacy is influenced by other immune escape associated factors, such as tumor antigenicity, apostolicity of tumor cells, and co-stimulatory signals. Appropriate treatment strategies should be put forward towards those impact factors.
Treatment can recover the expression of Class I HLA molecules. In other words, the deletion belongs to the above-mentioned reversible type. Immunotherapy can lead to local release of cytokines produced from TH1 T-cells in the tumor microenvironment, such as IFN-α and IFN-γ, which reversely upregulate Class I HLA molecule expression on tumor cells and the tumor antigens presented by the class-I HLA molecules can re-activate specific T cells to recognize and kill tumor cells. Studies have shown a positive correlation between expression recovery of Class I HLA molecules and immunotherapy efficacy on tumors [11, 20, 21].Treatment cannot recover the expression of Class I HLA molecules since the deletion belongs to the above-mentioned irreversible type. Immunotherapy is generally ineffective on tumors with such type of deletion, and the effort in the future is to find a way of increasing the expression of Class I HLA molecules. For instance, blocking antibodies for immune checkpoint usually have no effect on patients with mutated β2M and LOH on chromosome 15, which can cause inefficient antigen presentation [11, 22, 23].Expression of Class I HLA molecules is restorable, while the treatment itself has no impact on its expression. In order to have a better clinical effect in such a situation, other methods are required to enhance the expression of Class I HLA molecules. Therefore, it is imperative to identify the types of Class I HLA deletion for the prediction of therapeutic efficiency.4. The Relation Between Selective Pressure of Immunocyte and Changes of Class-I HLA Expression Pattern in Tumor Cells
Tumor cells are evolved from normal cells containing a positive expression of Class I HLA molecules. Loss of class-I HLA molecules occurs during the progressive development of neoplasms. Studies have shown that deletion is a gradual process with different cellular clones and various expression levels of class-I HLA molecules. AT the 12th International Conference on HLA, Garrido et al. proposed that tumor tissue could be classified into three types based on the expression of class-I HLA molecules, including positive, heterozygosity, and negative types. It is commonly believed that these three types of tumors reflect the transformation process of class-I HLA molecule expression from positive to negative. Tumor cells display positive expression at the early stage of tumor formation, and then heterozygous state with the gradual appearance of negative clones. Pure negative state indicates a late stage of tumorigenesis. Tumor cell clones with positive expression of class-I HLA molecules can be recognized and destroyed by activated anti-tumor T-cells. However, tumor cell clones of negative expression gradually form through a mechanism such as mutation and escape from recognition and elimination. As a result, only clones with negative expression of class-I HLA molecules finally remain in tumor tissues under such selective pressure [11, 24, 25].
Many kinds of researches have demonstrated a positive correlation between expression of class-I HLA molecules and the infiltration of immune cells, such as T-cells and M1 cells in tumor tissues. During the development of tumorigenesis, tumor cells gradually lose class-I HLA molecules accompany structure change of tumor tissue. In a positive and heterozygous state, there are lymphocytes and macrophages infiltrated in the tumor tissue due to the ability of class-I HLA molecule expressed cells to activate T-cells. However, in a negative expression state, the tumor tissues have deficient infiltration of immune cells, and tumor cells with class-I HLA molecules locate at tumor surrounding stroma region, forming an obvious boundary from negatively expressed tumor cells in the center of the lesion. Meanwhile, many fibroblasts emerge in peritumoral tissues, which mix with various immune cells to form a granulomatous structure of tumor tissue surrounded by non-neoplastic tissues. Such kind of granulomatous structure can be observed in many tumors, which continue to progress due to the inactive state of surrounding immune cells [15, 25, 26].
Although studies are still limited, comparison of class-I HLA molecule expression between metastatic and primary tumor tissues can inspire additional perspectives: 1) metastases with either expressed or not expressed class-I HLA molecules can derive from both primary tumor with positive and negative expression of class-I HLA molecules; 2) the type of deletion in metastatic and primary tumors can be same or different; 3) metastases can have a complete positive expression of class-I HLA molecules even if the primary lesion is negative. These interesting phenomena suggest that selective pressure posed by T-cells and NK cells plays an important role in the expression state of class-I HLA molecules in metastases and primary tumors [11, 27, 28].
There is also a relationship between the expression level of class-I HLA molecules in metastases and the immune status of the body. In the immunosuppressive state, metastasis can be induced, and then an expression of class-I HLA molecules can be restored as well. Studies in mouse models revealed that among multiple tumor cell clones, H-2 positive clones have higher immunogenicity and metastatic ability in comparison to H-2 negative clones. More significantly, sarcoma cell clones with reversible deletion of class-I HLA molecules after induction of IFN could enter a state of so-called immune quiescence in mice with normal immune function. However, metastases with positive expressed class-I HLA molecules were formed after T-cell deficiency was induced in mice. Immune quiescence refers to a static condition that tumor cells are neither progressive nor destroyed by the immune system. The status of equilibrium between tumor cells and the body's immune system can be maintained for a long period of time without any clinical symptoms unless the body immunity is decreased [11, 29-31].
EXPRESSION LEVELS OF NONCLASSICAL MHC CLASS I AND TUMOR IMMUNE ESCAPE
1. The HLA Class I Antigen Expression and Cancer
The HLA class I antigens play essential roles in immune response, for example, HLA can present peptide to T-cells and serve for ligands for a panel of receptors expressed on immune cells. Based on the tissue expression pattern, genetic polymorphism, and molecular function, HLA class I antigens can be grouped as the classical (HLA Ia for HLA-A, -B, and -C) and nonclassical antigens (HLA Ib for HLA-E, -F and -G). Unlike highly polymorphic and ubiquitously expressed HLA Ia antigens on nucleated cells, HLA Ib molecules have features such as limited tissue localization, low genetic diversity, limited peptide repertoire, and distinct functional profiles [32]. In the context of malignancies, alternation of HLA Ia antigen expression abnormalities can escape from host anti-tumor immune responses while induction of HLA Ib antigen expression on cancer cells can be involved in HLA Ib antigens to bind immunoinhibitory receptors such as immunoglobulin-like transcripts (ILT)2, ILT4 and NK receptor group 2 (NKG2) [33].
2. Roles of HLA Ib Antigens in Immune Modulation
The nonclassical HLA I antigens HLA-E, HLA-F, and HLA-G, were identified during the late 1980s. Contrary to the high polymorphic of HLA Ia antigens, only 43, 44, and 69 alleles with 11, 6, and 19 different proteins for HLA-E, HLA-F, and HLA-G, respectively (http://hla.alleles.org/nomenclature/stats.html). During the past three decades, the biological function and related clinical significance of HLA-E and HLA-G have been widely investigated in various physiological and pathological conditions [33].
HLA-E binds to the inhibitory receptors CD94/NKG2A and the activating receptor CD94/NKG2C. However, HLA-E preferentially binds to the inhibitory receptor CD94/NKG2A with much higher avidity than that of the activating receptor CD94/NKG2C. Consequently, HLA-E interacts with CD94/NKG2A can inhibit the activation and proliferation of NK cells and impair survival of the CD8+ tumor-infiltrating T lymphocytes in the tumor microenvironment [34].
HLA-G is the most intensively investigated molecule among the HLA Ib family, and seven HLA-G isoforms (HLA-G1~ HLA-G7) generated by its primary transcripts alternative splicing have been identified. Isoforms HLA-G1~HLA-G4 are membrane-bound while HLA-G5~HLA-G7 is soluble. Different HLA-G isoforms are distinguished by the number of extracellular immunoglobulin-like domains and by the transmembrane residues they have or not. HLA-G1 is encoded by the full-length HLA-G mRNA, and with three extracellular immunoglobulin-like domains (α1, α2, and α3), other isoforms may lack the α2, α3 domain or both, respectively. HLA-G can render comprehensive immune suppressive function by binding to receptors such as ILT2 and ILT4. ILT2 can be expressed on B-cell, T cells, NK cells, DCs, myeloid-derived suppressive cells (MDSCs), and monocytes, while ILT4 is expressed on DCs and monocytes, neutrophils and MDSCs. HLA-G/ILT2/4 inhibitory signal pathway can impair immune cell proliferation, differentiation, cytotoxicity, cytokine secretion, and chemotaxis. Moreover, HLA-G/ILT2/4 interaction can induce regulatory cells and promote the generation of MDSCs or polarization of M1 type macrophage to the M2 type. ILT2/4 recognizes HLA-G in its extra cellar α3 domain. However, the binding specificity of ILT2 and ILT4 is different according to the structure of the HLA-G molecule, that ILT4 recognizes both HLA-G associated with β2M and free HLA-G heavy chains, whereas ILT2 only recognizes HLA-G associated with β2M [35]. Given immune-suppressive functions resulted from the HLA-E and HLA-G and the interaction of their receptors in cancer immunology, HLA-G/ILT2/4 and HLA-E/NKG2A signaling pathway have been proposed as new immune checkpoints as the well established cytotoxic T lymphocyte-associated protein 4 (CTLA-4)/B7 and programmed cell death protein-1 (PD-1)/PD-L1. Antibodies target to these immune checkpoints can restore or re-activate T-cell and NK cell anti-tumor responses. Several approaches based on the HLA-G/ILT2/4 and HLA-E/NKG2A signaling pathway are currently under development for cancer immunotherapy [36, 37].
HLA-F is the least investigated molecule among HLA Ib antigens until recent data addressed that HLA-F can interact with either activating or inhibitory receptors on immune cells, depending on the conformation of HLA-F molecule. ILT2 and ILT4 can bind HLA-F/β2m/peptide complex through a docking strategy that precludes HLA-F open conformer recognition. However, KIRs (3DL1, 3DL2, 3DS1, and 2DS4) can bind HLA-F open conformer, where KIR3DS1 is of the highest binding affinity for HLA-F open conformer [38, 39]. These important findings Therefore, it is imperative to identifyprovide new evidence that HLA-F functions as an important immune regulatory molecule in human physiological and pathological conditions have been emerging. Though relative information of HLA-F/KIRs in cancer immunology is limited, the biological significance of HLA-F/KIR3DS1 in the viral infectious diseases has been highlighted in recent studies. For example, HLA-F open conformer /KIR3DS1 interaction can activate NK cell function in the control of viruses such as HIV and HCV replication [39, 40]. However, the inhibitory pathway between HLA-F/β2m/peptide complex/ILTs and HLA-F open conformer/KIR3DL1 remains to be investigated.
3. Clinical Relevance of HLA Ib Expression in Cancers
Cancer cells harness different strategies to escape surveillance from host both adaptive and innate anti-tumor immune responses. Abnormal expression and impaired function of HLA antigens on tumor cells frequently occurred in cancer immune evasion. In most cases, accompany with HLA Ia antigens down-regulated high-regulation of HLA-E, -F and -G have been detected in a wide variety of cancers associated with the progression and unfavorable clinical outcome of tumor diseases [41].
HLA-E expression has been found in many types of cancers, such as breast cancer, cervical cancer, colorectal cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, lung cancer, melanoma, renal cancer, thyroid cancer, and vulvar squamous cell carcinoma. Among these studies, increased HLA-E expression in cancer lesions has been observed to be related to the cancer cell metastasis, recruitment of regulatory immune cells, or associated with a worse prognosis in various cancer patients [33]. HLA-F expression has been observed in breast cancer, bladder cancer, oesophageal squamous cell cancer, gastric cancer, hepatocellular carcinoma, nasopharyngeal cancer, neuroblastoma, and lung cancer. Among these studies, HLA-F expression in gastric adenocarcinoma has observed to be significantly correlated with the depth of invasion, nodal involvement, lymphatic and venous invasions, and with a worse prognosis [42]. In patients with HLA-F positive had a worse survival than those with HLA-F negative. In another study, upregulated HLA-F expression (lesion vs. normal tissue) was found to have significantly worse survival than those with HLA-F unchanged and downregulated in patients with oesophageal squamous cell carcinoma [43].
HLA-G expression in cancers was firstly reported in 1998. Later, HLA-G expression has been analyzed and evaluated worldwide in thousands of malignant samples with various types of cancers such as breast cancer, colorectal cancer (CRC), cervical cancer, endometrial cancer, oesophageal squamous cell carcinoma (ESCC), Ewing sarcoma, gastric cancer, glioblastoma, HCC, lung cancer, lymphoma, nasopharyngeal carcinoma, oral squamous cell carcinoma, ovarian cancer, pancreatic adenocarcinoma, thyroid cancer, and vulvar squamous cell carcinoma. Aberrant HLA-G expression in cancers has been found to be associated with advanced tumor stage, metastasis, and worse prognosis [35].
4. Prospective of HLA-E and HLA-G Targeted Cancer Immunotherapy
Cancer therapy has made significant improvements due to the development of new approaches to increase anti-tumor immune responses. Tumor immunotherapies currently are mainly focused on the antibodies (Ab) to block immune checkpoints such as CTLA-4 and PD-1 to restore or re-activate T-cell anti-tumor immune responses, or the generation of T cells expressing chimeric antigen receptor (CARs) specific for tumor antigens. However, but only nearly 20% of patients received the benefit from the targeted cancer immunotherapy. Therefore, combination therapy for targeting immune checkpoint pathways could significantly increase therapeutic response [44]. Indeed, besides the well-acknowledged CTLA-4/B7 and PD-1/PD-L1 signaling pathway, other potential immune checkpoints such as HLA-G/ILT2/4 and HLA-E/NKG2A signaling pathway blockade are currently under development or clinical trial for cancer immunotherapy [33].
Protein expression blockers (PEBLs) by constructs containing a single-chain variable fragment derived from an anti-NKG2A antibody can block NKG2A expression on NK cells. Kamiya et al. reported that NKG2A null NK cells had higher cytotoxicity against HLA-E+ tumor cells [45]. Furthermore, André et al. [46] recently reported that HLA-E-specific inhibitory receptor NKG2A is an important checkpoint on NK and CD8+ T cells. NKG2A blocked with Monalizumab can restore the anti-tumor function of NKG2A+ NK and T-cells. Moreover, combination with the anti-PD-L1 blocking mAb (Durvalumab) has a synergistic effect in NKG2A+ and PD-1+ NK cells against HLA-E+ and PD-L1+ target cells, which can further improve the control of tumor growth and mice from death.
Cancer immune therapy based on the HLA-G/ILT2/4 immune checkpoint pathway has been proposed in vivo studies. In previous preclinical investigations, restoring the functions of NK cell or T-cell against target cancer cells has been observed with blocking tumor cell-expressed HLA-G or immune cell surface ILT2/4 with specific mAbs [35]. Moreover, the generation of T cells to express chimeric antigen receptors (CAR) specific for HLA-G are currently under development for cancer immunotherapy.
However, a few critical aspects should be taken into consideration before application in a clinical trial. First, the inter-tumor and intratumor heterogeneity of HLA-E/G expression vary dramatically, as indicated in numerous previous studies. Second, at least seven HLA-G isoforms have been identified so that HLA-G and ILT2/4 binding depends on the molecular structure of the different molecular structures of HLA-G isoforms make the HLA-G /ILT2/4 signaling pathway even more complex.
