Journal Articles

Immunotherapy design

Novel approaches and designs of biologicals used for cancer immunotherapy as well as changes in the timing, combination sequence, adjuvant choice or route of immunization in immunotherapy regimens; biomarkers of response to therapy

Engineering PD-1-Presenting Platelets for Cancer Immunotherapy

More

Radical surgery still represents the treatment choice for several malignancies. However, local and distant tumor relapses remain the major causes of treatment failure, indicating that a postsurgery consolidation treatment is necessary. Immunotherapy with checkpoint inhibitors has elicited impressive clinical responses in several types of human malignancies and may represent the ideal consolidation treatment after surgery. Here, we genetically engineered platelets from megakaryocyte (MK) progenitor cells to express the programmed cell death protein 1 (PD-1). The PD-1 platelet and its derived microparticle could accumulate within the tumor surgical wound and revert exhausted CD8(+) T cells, leading to the eradication of residual tumor cells. Furthermore, when a low dose of cyclophosphamide (CP) was loaded into PD-1-expressing platelets to deplete regulatory T cells (Tregs), an increased frequency of reinvigorated CD8(+) lymphocyte cells was observed within the postsurgery tumor microenvironment, directly preventing tumor relapse.

Author Info: (1) Guangdong Key Laboratory for Biomedical, Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science Center , Shenzhen University

Author Info: (1) Guangdong Key Laboratory for Biomedical, Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science Center , Shenzhen University , Shenzhen 518060 , China. Department of Bioengineering, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics (C-MIT) , University of California , Los Angeles , California 90095 , United States. Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (2) Department of Bioengineering, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics (C-MIT) , University of California , Los Angeles , California 90095 , United States. Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (3) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (4) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (5) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (6) Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States. (7) Lineberger Comprehensive Cancer Center , University of North Carolina , Chapel Hill , North Carolina 27599 , United States. (8) Guangdong Key Laboratory for Biomedical, Measurements and Ultrasound Imaging, Laboratory of Evolutionary Theranostics, School of Biomedical Engineering, Health Science Center , Shenzhen University , Shenzhen 518060 , China. (9) Department of Bioengineering, California NanoSystems Institute, and Center for Minimally Invasive Therapeutics (C-MIT) , University of California , Los Angeles , California 90095 , United States. Joint Department of Biomedical Engineering , University of North Carolina at Chapel Hill and North Carolina State University , Raleigh , North Carolina 27695 , United States.

Less

Activation of phagocytosis by immune checkpoint blockade

More

Inhibition of macrophage-mediated phagocytosis has emerged as an essential mechanism for tumor immune evasion. One mechanism inhibiting the innate response is the presence of the macrophage inhibitory molecule, signal regulatory protein-alpha (SIRPalpha), on tumor-associated macrophages (TAMs) and its cognate ligand cluster of differentiation 47 (CD47) on tumor cells in the tumor microenvironment. On the basis of a recently discovered programmed death protein 1 (PD-1) in TAMs, we discuss the potential inhibitory receptors that possess new functions beyond T cell exhaustion in this review. As more and more immune receptors are found to be expressed on TAMs, the corresponding therapies may also stimulate macrophages for phagocytosis and thereby provide extra anti-tumor benefits in cancer therapy. Therefore, identification of biomarkers and combinatorial therapeutic strategies, have the potential to improve the efficacy and safety profiles of current immunotherapies.

Author Info: (1) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (2) Department of Neurology, McGovern Medical

Author Info: (1) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (2) Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA. (3) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. (4) Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. mhung@mdanderson.org.

Less

Dendritic cells loaded with the lysate of tumor cells infected with Newcastle Disease Virus trigger potent anti-tumor immunity by promoting the secretion of IFN-gamma and IL-2 from T cells

More

Dendritic cells (DCs) are professional antigen-presenting cells that are pivotal in the generation and sustainability of antitumor immune responses. Whole tumor cell lysates (TCLs) have been used as sources of tumor antigens for the development of DC vaccines. However, the clinical outcomes of the use of TCL-based DC vaccines have so far been unsatisfactory because of the weak immunogenicity of tumor cells. To improve the efficacy of TCL-based DC vaccines, viruses have been used to enhance the immunity of TCLs and to further enhance the antigen delivery and antigen-presenting ability of DCs. The aim of the present study was to improve the antigen-presenting ability of DCs and to use them to effectively activate T lymphocytes. The present study demonstrated that DCs loaded with the lysate of Newcastle Disease Virus (NDV)-infected tumor cells (NDV-TCL) have increased levels of cluster of differentiation 80 (CD80), CD86, CD83 and human leukocyte antigen-antigen D-associated expression, compared with those loaded with TCL alone. The DCs loaded with the NDV-TCL promoted T-cell proliferation and antitumor cytokine secretion from T cells. These results indicated that loading DCs with NDV-TCL could enhance the antigen-presenting ability of the DCs. On the basis of the results of the present study, we hypothesize that this method of loading DCs with NDV-TCL can be used to develop novel DC vaccines for tumor immunotherapy in the future.

Author Info: (1) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and

Author Info: (1) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. State Key Laboratory on Integrated Optoelectronics, College of Electronic Science and Engineering, Jilin University, Changchun, Jilin 130012, P.R. China. (2) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. (3) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. (4) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. (5) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. (6) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. (7) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. (8) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China. (9) Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.

Less

Glyco-Engineered Anti-Human Programmed Death-Ligand 1 Antibody Mediates Stronger CD8 T Cell Activation Than Its Normal Glycosylated and Non-Glycosylated Counterparts

More

The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis plays a central role in suppression of anti-tumor immunity. Blocking the axis by targeting PD-L1 with monoclonal antibodies is an effective and already clinically approved approach to treat cancer patients. Glyco-engineering technology can be used to optimize different properties of monoclonal antibodies, for example, binding to FcgammaRs. We generated two glycosylation variants of the same anti-PD-L1 antibody: one bearing core fucosylated N-glycans in its Fc part (92%) and its de-fucosylated counterpart (4%). The two glycosylation variants were compared to a non-glycosylated commercially available anti-PD-L1 antibody in various assays. No differences were observed regarding binding to PD-L1 and blocking of this interaction with its counter receptors PD-1 or CD80. The de-fucosylated anti-PD-L1 antibody showed increased FcgammaRIIIa binding resulting in enhanced antibody dependent cellular cytotoxicity (ADCC) activity against PD-L1(+) cancer cells compared to the "normal"-glycosylated variant. Both glycosylation variants showed no antibody-mediated lysis of B cells and monocytes. The non-glycosylated reference antibody showed no FcgammaRIIIa engagement and no ADCC activity. Using mixed leukocyte reaction it was observed that the de-fucosylated anti-PD-L1 antibody induced the strongest CD8 T cell activation determined by expression of activation markers, proliferation, and cytotoxicity against cancer cells. The systematic comparison of anti-PD-L1 antibody glycosylation variants with different Fc-mediated potencies demonstrates that our glyco-optimization approach has the potential to enhance CD8 T cell-mediated anti-tumor activity which may improve the therapeutic benefit of anti-PD-L1 antibodies.

Author Info: (1) Glycotope GmbH, Berlin, Germany. (2) Glycotope GmbH, Berlin, Germany. (3) Glycotope GmbH, Berlin, Germany. (4) Glycotope GmbH, Berlin, Germany. (5) Glycotope GmbH, Berlin, Germany

Author Info: (1) Glycotope GmbH, Berlin, Germany. (2) Glycotope GmbH, Berlin, Germany. (3) Glycotope GmbH, Berlin, Germany. (4) Glycotope GmbH, Berlin, Germany. (5) Glycotope GmbH, Berlin, Germany. (6) Glycotope GmbH, Berlin, Germany. (7) Glycotope GmbH, Berlin, Germany.

Less

Combining vaccines and immune checkpoint inhibitors to prime, expand, and facilitate effective tumor immunotherapy

More

INTRODUCTION: Multiple immune checkpoint inhibitors (ICIs) that modulate immune cells in the periphery and the tumor microenvironment (TME) have been approved, as have the therapeutic cancer vaccines sipuleucel-T for metastatic castration-resistant prostate cancer and talimogene laherparepvec (T-VEC) for metastatic melanoma. These developments provide rationale for combining these modalities in order to improve response rates and durability of responses in a variety of cancers. Preclinical data have shown that vaccines can induce immune responses that turn a tumor from "cold" to "hot," but vaccines do not appear to be highly active as monotherapy. Areas covered: Here we provide a review of the current state of vaccine and ICI combination studies. Expert commentary: Most combination trials are in early phases, but several are now in phase III. Vaccines that target antigens expressed exclusively on tumor cells, neoantigens, have the potential to induce robust antitumor responses. Several techniques for predicting which neoepitopes to target, based on tumor mutational profiling, are in various stages of development. In order to be successful, combination immunotherapy approaches must seek to prime the immune system, expand the immune response, and facilitate immune function within the TME.

Author Info: (1) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA. (2) a

Author Info: (1) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA. (2) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA. (3) a Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute , National Institutes of Health , Bethesda , MD , USA.

Less

Quantification and functional evaluation of CD40L production from the adenovirus vector ONCOS-401

More

Adaptive immunity involves activation of T cells via antigen presentation by antigen presenting cells (APCs) along with the action of co-stimulatory molecules and pattern recognition receptors. Cluster of differentiation 40 (CD40) is one such costimulatory molecule that is expressed on APCs that binds to CD40 ligand (CD40L) on T helper cells and activates a signaling cascade, subsequently resulting in a wide range of immune and inflammatory responses. Considering its important role in regulation of immune response, CD40/40 L has been used for developing antitumor vaccines. In this study, we developed methods for evaluating and quantifying the activity of CD40L expressed from an adenovirus vector ONCOS-401. Our results show that the ONCOS-401 vector produces functional CD40L, which can bind and activate a NF-kappaB-dependent signaling cascade, leading to secreted embryonic alkaline phosphatase reporter production in HEK293-BLUE cells. In addition, quantification of CD40L production using enzyme-linked immunosorbent assay and HEK-293 BLUE reporter cells showed reproducibly higher recovery of CD40L from ONCOS-401 than from the negative control vector or uninfected cells with consistent inter and intra-assay precision. Thus, a rapid and easy method for quantifying and assessing CD40L production and activity from adenovirus vectors would support the assessment of efficacy of the vector for gene therapy - this was the objective of our study.

Author Info: (1) Targovax Oy, Clinical Science, Helsinki, Finland. lukasz.kuryk@targovax.com. Department of Virology, National Institute of Public Health-National Institute of Hygiene, Warsaw, Poland. lukasz.kuryk@targovax.com. (2) Targovax ASA

Author Info: (1) Targovax Oy, Clinical Science, Helsinki, Finland. lukasz.kuryk@targovax.com. Department of Virology, National Institute of Public Health-National Institute of Hygiene, Warsaw, Poland. lukasz.kuryk@targovax.com. (2) Targovax ASA, Clinical Science, Oslo, Norway. (3) Targovax ASA, Clinical Science, Oslo, Norway.

Less

NK cell-mediated anti-leukemia cytotoxicity is enhanced using a NKG2D ligand MICA and anti-CD20 scfv chimeric protein

More

Natural killer (NK) cells are important innate cytotoxic lymphocytes that have potential in treatment of leukemia. Engagement of NKG2D receptor on NK cells enhances the target cytotoxicity. Here we produced a fusion protein consisting of the extracellular domain of the NKG2D ligand MICA and the anti-CD20 single-chain variable fragment (scfv). This recombinant protein is capable of binding both NK cells and CD20(+) tumor cells. Using a human NKG2D reporter cell system we developed, we showed that this fusion protein could decorate CD20(+) tumor cells with MICA extracellular domain and activate NK through NKG2D. We further demonstrated that this protein could specifically induce the ability of a NK cell line (NKL) and primary NK cells to lyse CD20(+) leukemia cells. Moreover, we found that down-regulation of surface HLA class I expression in the target cells improved NKL-mediated killing. Our results demonstrated that this recombinant protein specifically lyses leukemia cells by NK cells may lead to development of a novel strategy for treating leukemia and other tumors. This article is protected by copyright. All rights reserved.

Author Info: (1) Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan, China, 410005. (2) Department of Immunology, School of Basic Medical Science

Author Info: (1) Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan, China, 410005. (2) Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan, China, 410005. Department of Physiology, UT Southwestern Medical Center at Dallas, TX, 75390. (3) Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan, China, 410005. (4) Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan, China, 410005. (5) Department of Physiology, UT Southwestern Medical Center at Dallas, TX, 75390. (6) Department of Physiology, UT Southwestern Medical Center at Dallas, TX, 75390. (7) Department of Physiology, UT Southwestern Medical Center at Dallas, TX, 75390. (8) Department of Physiology, UT Southwestern Medical Center at Dallas, TX, 75390.

Less

Cancer Stem Cell Vaccination With PD-L1 and CTLA-4 Blockades Enhances the Eradication of Melanoma Stem Cells in a Mouse Tumor Model

More

Immune checkpoint inhibitors and monoclonal antibodies reinvigorate cancer immunotherapy. However, these immunotherapies only benefit a subset of patients. We previously reported that ALDH tumor cells were highly enriched for cancer stem cells (CSCs), and ALDH CSC lysate-pulsed dendritic cell (CSC-DC) vaccine was shown to induce CSC-specific cytotoxic T lymphocytes. In this study, we investigated the CSC targeting effect of the CSC-DC vaccine combined with a dual blockade of programmed death-ligand 1 and cytotoxic T-lymphocyte-associated protein (CTLA-4) in B16-F10 murine melanoma tumor model. Our data showed that animals treated with the dual blockade of programmed death-ligand 1 and CTLA-4 and CSC-DC vaccine conferred significantly more tumor regression than the CSC-DC vaccine alone. Importantly, the triple combination treatment dramatically eliminated ALDH CSCs in vivo. We observed that CSC-DC vaccine in combination with anti-PD-L1 and anti-CTLA-4 administration resulted in approximately 1.7-fold fewer PD-1CD8 T cells and approximately 2.5-fold fewer CTLA-4CD8 T cells than the populations observed following the CSC-DC vaccination alone. Moreover, significant antitumor effects and dramatically eliminated ALDH CSCs following the triple combination treatment were accompanied by significantly enhanced T-cell expansion, suppressed transforming growth factor beta secretion, enhanced IFN-gamma secretion, and significantly enhanced host specific CD8 T-cell response against CSCs. Collectively, these data showed that administration of a-PD-L1 and a-CTLA-4 combined with CSC-DC vaccine may represent an effective immunotherapeutic strategy for cancer patients in clinical.

Author Info: (1) Department of Pediatrics. (2) Department of Geriatrics, Renmin Hospitial of Wuhan University, Wuhan. (3) Department of Hematology. (4) The Clinical Trial Institute, Peking University

Author Info: (1) Department of Pediatrics. (2) Department of Geriatrics, Renmin Hospitial of Wuhan University, Wuhan. (3) Department of Hematology. (4) The Clinical Trial Institute, Peking University Shenzhen Hospital, Shenzhen. (5) Department of Pediatrics. (6) Department of Pediatrics. (7) Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. (8) Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. (9) Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI. (10) Department of Surgery, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI.

Less

CD28-zeta CAR T Cells Resist TGF-beta Repression through IL-2 Signaling, Which Can Be Mimicked by an Engineered IL-7 Autocrine Loop

More

Adoptive cell therapy with chimeric antigen receptor (CAR)-redirected T cells induced spectacular regressions of leukemia and lymphoma, however, failed so far in the treatment of solid tumors. A cause is thought to be T cell repression through TGF-beta, which is massively accumulating in the tumor tissue. Here, we show that T cells with a CD28-zeta CAR, but not with a 4-1BB-zeta CAR, resist TGF-beta-mediated repression. Mechanistically, LCK activation and consequently IL-2 release and autocrine IL-2 receptor signaling mediated TGF-beta resistance; deleting the LCK-binding motif in the CD28 CAR abolished both IL-2 secretion and TGF-beta resistance, while IL-2 add-back restored TGF-beta resistance. Other gamma-cytokines like IL-7 and IL-15 could replace IL-2 in this context. This is demonstrated by engineering IL-2 deficient CD28DeltaLCK-zeta CAR T cells with a hybrid IL-7 receptor to provide IL-2R beta chain signaling upon IL-7 binding. Such modified T cells showed improved CAR T cell activity against TGF-beta(+) tumors. Data draw the concept that an autocrine loop resulting in IL-2R signaling can make CAR T cells more potent in staying active against TGF-beta(+) solid tumors.

Author Info: (1) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany. (2) Center for Molecular Medicine

Author Info: (1) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany. (2) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany. (3) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany. (4) Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; Department I Internal Medicine, University Hospital Cologne, Cologne, Germany; Regensburg Center for Interventional Immunology (RCI), University Regensburg, Regensburg, Germany; University Medical Center of Regensburg, Regensburg, Germany. Electronic address: hinrich.abken@ukr.de.

Less

Cytotoxic activity of effector T cells against cholangiocarcinoma is enhanced by self-differentiated monocyte-derived dendritic cells

More

Cholangiocarcinoma (CCA) is a cancer of the bile ducts that is associated with poor prognosis and poor treatment outcome. Approximately one-third of CCA patients can undergo surgery, but the recurrence rate is high and chemotherapy often cannot satisfactorily prolong survival. Cellular immunotherapy based on adoptive T-cell transfer is a potential treatment for CCA; however, the development of this technology and the search for an appropriate tumor-associated antigen are still ongoing. To enhance the cytotoxic activity of effector T cells against CCA, we developed self-differentiated monocyte-derived dendritic cells (SD-DC) presenting cAMP-dependent protein kinase type I-alpha regulatory subunit (PRKAR1A), which is an overexpressed protein that plays a role in the regulation of tumor growth to activate T cells for CCA cell killing. Dendritic cells (DCs) transduced with lentivirus harboring tri-cistronic cDNA sequences (SD-DC-PR) could produce granulocyte-macrophage colony-stimulating factor, interleukin-4, and PRKAR1A. SD-DC showed similar phenotypes to those of DCs derived by conventional method. Autologous effector T cells (CD3+, CD8+) activated by SD-DC-PR exhibited greater cytotoxic activity against CCA than those activated by conventionally-derived DCs. Effector T cells activated by SD-DC-PR killed 60% of CCA cells at an effector-to-target ratio of 15:1, which is approximately twofold greater than the cell killing performance of those stimulated with control DC. The cytotoxic activities of effector T cells activated by SD-DC-PR against CCA cells were significantly associated with the expression levels of PRKR1A in CCA cells. This finding that SD-DC-PR effectively stimulated autologous effector T cells to kill CCA cells may help to accelerate the development of novel therapies for treating CCA.

Author Info: (1) Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand. Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj

Author Info: (1) Department of Biology, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand. Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. Center of Excellence in Bioresources for Agriculture, Industry and Medicine, Faculty of Science, Chiang Mai University, Chiang Mai, Thailand. (2) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (3) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. (4) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. (5) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. Graduate Program in Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. (6) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. (7) Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. Cholangiocarcinoma Research Institute, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. (8) Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), 4th Floor Siriraj Medical Research Center (SiMR), Faculty of Medicine Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand. pathai.yen@mahidol.ac.th.

Less