Journal Articles

Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ

INTRODUCTION: Cancer is categorized into two types based on the microenvironment: cold and hot tumors. The former is challenging to stimulate through immunity. The immunogenicity of cancer relies on the quality and quantity of cancer antigens, whether recognized by T cells or not. Successful cancer immunotherapy hinges on the cancer cell type, antigenicity and subsequent immune reactions. The T cell response is particularly crucial for secondary epitope spreading, although the factors affecting these mechanisms remain unknown. Prostate cancer often becomes resistant to standard therapy despite identifying several antigens, placing it among immunologically cold tumors. We aim to leverage prostate cancer antigens to investigate the potential induction of epitope spreading in cold tumors. This study specifically focuses on identifying factors involved in secondary epitope spreading based on artificial adjuvant vector cell (aAVC) therapy, a method established as invariant natural killer T (iNKT) -licensed DC therapy. METHODS: We concentrated on three prostate cancer antigens (prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP)). By introducing allogeneic cells with the antigen and murine CD1d mRNA, followed by _-galactosylceramide (_-GalCer) loading, we generated five types of aAVCs, i.e, monovalent, divalent and trivalent antigen-expressing aAVCs and four types of prostate antigen-expressing cold tumors. We evaluated iNKT activation and antigen-specific CD8+ T cell responses against tumor cells prompted by the aAVCs. RESULTS: Our study revealed that monovalent aAVCs, expressing a single prostate antigen, primed T cells for primary tumor antigens and also induced T cells targeting additional tumor antigens by triggering a tumor antigen-spreading response. When we investigated the immune response by trivalent aAVC (aAVC-PROS), aAVC-PROS therapy elicited multiple antigen-specific CD8+ T cells simultaneously. These CD8+ T cells exhibited both preventive and therapeutic effects against tumor progression. CONCLUSIONS: The findings from this study highlight the promising role of tumor antigen-expressing aAVCs, in inducing efficient epitope spreading and generating robust immune responses against cancer. Our results also propose that multivalent antigen-expressing aAVCs present a promising therapeutic option and could be a more comprehensive therapy for treating cold tumors like prostate cancer.

Author Info: (1) Laboratory for Immunotherapy, RIKEN Research Center for Integrative Medical Science (IMS), Yokohama, Japan. (2) Laboratory for Immunotherapy, RIKEN Research Center for Integrat

Author Info: (1) Laboratory for Immunotherapy, RIKEN Research Center for Integrative Medical Science (IMS), Yokohama, Japan. (2) Laboratory for Immunotherapy, RIKEN Research Center for Integrative Medical Science (IMS), Yokohama, Japan. aAVC Drug Translational Unit, RIKEN Center for Integrative Medical Science (IMS), Yokohama, Japan. (3) Laboratory for Immunotherapy, RIKEN Research Center for Integrative Medical Science (IMS), Yokohama, Japan. aAVC Drug Translational Unit, RIKEN Center for Integrative Medical Science (IMS), Yokohama, Japan. RIKEN Program for Drug Discovery and Medical Technology Platforms, Yokohama, Japan.

BAMLET administration via drinking water inhibits intestinal tumor development and promotes long-term health

Though new targeted therapies for colorectal cancer, which progresses from local intestinal tumors to metastatic disease, are being developed, tumor specificity remains an important problem, and side effects a major concern. Here, we show that the protein-fatty acid complex BAMLET (bovine alpha-lactalbumin made lethal to tumor cells) can act as a peroral treatment for colorectal cancer. Apc(Min/+) mice, which carry mutations relevant to hereditary and sporadic human colorectal cancer, that received BAMLET in the drinking water showed long-term protection against tumor development and decreased expression of tumor growth-, migration-, metastasis- and angiogenesis-related genes. BAMLET treatment via drinking water inhibited the Wnt/_-catenin and PD-1 signaling pathways and prolonged survival without evidence of toxicity. Systemic disease in the lungs, livers, spleens, and kidneys, which accompanied tumor progression, was inhibited by BAMLET treatment. The metabolic response to BAMLET included carbohydrate and lipid metabolism, which were inhibited in tumor prone Apc(Min/+) mice and weakly regulated in C57BL/6 mice, suggesting potential health benefits of peroral BAMLET administration in addition to the potent antitumor effects. Together, these findings suggest that BAMLET administration in the drinking water maintains antitumor pressure by removing emergent cancer cells and reprogramming gene expression in intestinal and extra-intestinal tissues.

Author Info: (1) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (2) Divisi

Author Info: (1) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (2) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (3) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (4) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (5) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (6) Department of Pathology and Molecular Medicine, Motol University Hospital, 2nd Faculty of Medicine, Charles University Praha, 150 06, Prague, Czech Republic. (7) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (8) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (9) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (10) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. (11) Division of Microbiology, Immunology and Glycobiology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, Klinikgatan 28, 221 84, Lund, Sweden. catharina.svanborg@med.lu.se.

Extracorporeal photopheresis as a promising strategy for the treatment of GvHD after CAR-T cell therapy

Graft-versus-host disease (GvHD) occurs in about 10-33% of patients receiving "al-logeneic" or "autologous" CAR-T cells after preceding allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to the substantial presence of alloreactive T cells. Extracorporeal photopheresis (ECP) shows promising clinical outcomes in the treatment of GvHD after allo-HSCT without hampering anti-tumor and anti-viral effects. This raises an interesting question: whether ECP might constitute a new way to treat patients with GvHD after CAR-T cell therapy without compromising CAR-T cells significantly. Third-generation CD19-specific CAR-T cells were generated and an in vitro ECP protocol was established. The impact of ECP on CAR-T cells was comprehensively investigated in two models: the non-dilution model reflects days following CAR-T cell infusion and the dilution model weeks after infusion. The ther-apeutic effect of ECP on GvHD was examined in an in vitro mixed lymphocyte reac-tion (MLR) assay. We found out that ECP treated CAR-T cells demonstrated reduced potency in inducing alloreaction compared to the group without ECP treatment in MLR assay. ECP could selectively induce apoptosis, thereby enriching the naive and central memory CAR-T cells with a reduced alloreactivity. The cytokine milieu of CAR-T cells could be switched from immune stimulation to immune tolerance in both models. Moreover, ECP could modulate the proliferative capacity of CAR-T cells without hampering their long-term functionality in the dilution model. In con-clusion, ECP constitutes a promising treatment strategy for GvHD after allo-HSCT and CAR-T cell transfusion, as ECP reduces the alloreactivity without hampering CAR-T cell functionality.

Author Info: (1) University Clinic Heidelberg, Heidelberg, Germany, Heidelberg, Germany. (2) University Hospital Heidelberg, Heidelberg, Germany. (3) University Hospital Heidelberg, Heidelberg,

Author Info: (1) University Clinic Heidelberg, Heidelberg, Germany, Heidelberg, Germany. (2) University Hospital Heidelberg, Heidelberg, Germany. (3) University Hospital Heidelberg, Heidelberg, Germany. (4) UniversitŠtsklinikum Heidelberg, Heidelberg, Germany. (5) University Hospital Heidelberg, Heidelberg, Germany. (6) University Hospital Heidelberg, Heidelberg, Germany. (7) University Hospital Heidelberg, Heidelberg, Germany. (8) University Hospital Heidelberg, Heidelberg, Germany. (9) University Hospital Heidelberg, Heidelberg, Germany. (10) Heidelberg University Hospital, Heidelberg, Germany. (11) Shanxi Province Fenyang Hospital, Fenyang, China. (12) University Hospital Heidelberg, Heidelberg, Germany. (13) University Hospital Heidelberg, Heidelberg, Germany. (14) University of Heidelberg, Heidelberg, Germany.

Biologically Self-Assembled Tumor Cell-Derived Cancer Nanovaccines as an All-in-One Platform for Cancer Immunotherapy

Tumor cell-derived cancer nanovaccines introduce tumor cell-derived components as functional units that endow the nanovaccine systems with some advantages, especially providing all potential tumor antigens. However, cumbersome assembly steps, potential risks of exogenous adjuvants, as well as insufficient lymph node (LN) targeting and dendritic cell (DC) internalization limit the efficacy and clinical translation of existing tumor cell-derived cancer nanovaccines. Herein, we introduced an endoplasmic reticulum (ER) stress inducer _-mangostin (_M) into tumor cells through poly(d, l-lactide-co-glycolide) nanoparticles and harvested biologically self-assembled tumor cell-derived cancer nanovaccines (_M-Exos) based on the biological process of tumor cell exocytosing nanoparticles through tumor-derived exosomes (TEXs). Besides presenting multiple potential antigens, _M-Exos inherited abundant 70 kDa heat shock proteins (Hsp70s) upregulated by ER stress, which can not only act as endogenous adjuvants but also improve LN targeting and DC internalization. Following subcutaneous injection, _M-Exos efficiently migrated to LNs and was expeditiously endocytosed by DCs, delivering tumor antigens and adjuvants to DCs synchronously, which then powerfully triggered antitumor immune responses and established long-term immune memory. Our study exhibited an all-in-one biologically self-assembled tumor cell-derived cancer nanovaccine platform, and the fully featured cancer nanovaccines assembled efficiently through this platform are promising for desirable cancer immunotherapy.

Author Info: (1) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Educati

Author Info: (1) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China. (2) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China. (3) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China. (4) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China. (5) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China. (6) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China. (7) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China. (8) Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (9) Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (10) Department of Rheumatology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 201399, Shanghai, China. (11) School of Pharmacy, Fudan University, 201203 Shanghai, China. (12) Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Universities Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China. (13) Department of Pharmaceutics, School of Pharmacy & Shanghai Pudong Hospital, Fudan University, 201203 Shanghai, China. Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, 201203 Shanghai, China.

Hybrid Ginseng-derived Extracellular Vesicles-Like Particles with Autologous Tumor Cell Membrane for Personalized Vaccination to Inhibit Tumor Recurrence and Metastasis

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM-NPs) are formed by hybridizing ginseng-derived extracellular vesicles-like particles (G-EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G-EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor-specific cytotoxic T lymphocytes (CTLs). HM-NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long-term immune protection can be obtained after vaccinating with HM-NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G-EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility.

Author Info: (1) Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 21002

Author Info: (1) Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. (2) Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. (3) School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. (4) School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China. (5) Department of Dermatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China. (6) Chinatalentgroup (CTG Group), Beijing, 100020, China. (7) Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China. School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210023, China.

Enhancing Mass spectrometry-based tumor immunopeptide identification: machine learning filter leveraging HLA binding affinity, aliphatic index and retention time deviation

Accurately identifying neoantigens is crucial for developing effective cancer vaccines and improving tumor immunotherapy. Mass spectrometry-based immunopeptidomics has emerged as a promising approach to identifying human leukocyte antigen (HLA) peptides presented on the surface of cancer cells, but false-positive identifications remain a significant challenge. In this study, liquid chromatography-tandem mass spectrometry-based proteomics and next-generation sequencing were utilized to identify HLA-presenting neoantigenic peptides resulting from non-synonymous single nucleotide variations in tumor tissues from 18 patients with renal cell carcinoma or pancreatic cancer. Machine learning was utilized to evaluate Mascot identifications through the prediction of MS/MS spectral consistency, and four descriptors for each candidate sequence: the max Mascot ion score, predicted HLA binding affinity, aliphatic index and retention time deviation, were selected as important features in filtering out identifications with inadequate fragmentation consistency. This suggests that incorporating rescoring filters based on peptide physicochemical characteristics could enhance the identification rate of MS-based immunopeptidomics compared to the traditional Mascot approach predominantly used for proteomics, indicating the potential for optimizing neoantigen identification pipelines as well as clinical applications.

Author Info: (1) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan.

Author Info: (1) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan. (2) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan. (3) Isotope Science Center, The University of Tokyo, Tokyo, Japan. (4) Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. (5) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Research & Early Development Division, BrightPath Biotherapeutics Co., Ltd., Kawasaki, Japan. (6) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Research & Early Development Division, BrightPath Biotherapeutics Co., Ltd., Kawasaki, Japan. (7) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. (8) Department of Urology, Kanagawa Cancer Center, Yokohama, Japan. (9) Department of Hepato-Biliary and Pancreatic Surgery, Kanagawa Cancer Center, Yokohama, Japan. (10) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan. (11) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan. Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo, Japan. (12) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan. (13) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan. (14) Research & Early Development Division, BrightPath Biotherapeutics Co., Ltd., Kawasaki, Japan. (15) Isotope Science Center, The University of Tokyo, Tokyo, Japan. (16) Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan. Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center, Yokohama, Japan.

Humanized mouse model for vaccine evaluation: an overview

Animal models are essential in medical research for testing drugs and vaccines. These models differ from humans in various respects, so their results are not directly translatable in humans. To address this issue, humanized mice engrafted with functional human cells or tissue can be helpful. We propose using humanized mice that support the engraftment of human hematopoietic stem cells (HSCs) without irradiation to evaluate vaccines that influence patient immunity. For infectious diseases, several types of antigens and adjuvants have been developed and evaluated for vaccination. Peptide vaccines are generally used for their capability to fight cancer and infectious diseases. Evaluation of adjuvants is necessary as they induce inflammation, which is effective for an enhanced immune response but causes adverse effects in some individuals. A trial can be done on humanized mice to check the immunogenicity of a particular adjuvant and peptide combination. Messenger RNA has also emerged as a potential vaccine against viruses. These vaccines need to be tested with human immune cells because they work by producing a particular peptide of the pathogen. Humanized mice with human HSCs that can produce both myeloid and lymphoid cells show a similar immune response that these vaccines will produce in a patient.

Author Info: (1) All India Institute of Medical Sciences, New Delhi, India. (2) All India Institute of Medical Sciences, New Delhi, India. (3) All India Institute of Medical Sciences, New Delhi

Author Info: (1) All India Institute of Medical Sciences, New Delhi, India. (2) All India Institute of Medical Sciences, New Delhi, India. (3) All India Institute of Medical Sciences, New Delhi, India.

Engineered T cells secreting anti-BCMA T cell engagers control multiple myeloma and promote immune memory in vivo

Multiple myeloma is the second most common hematological malignancy in adults and remains an incurable disease. B cell maturation antigen (BCMA)-directed immunotherapy, including T cells bearing chimeric antigen receptors (CARs) and systemically injected bispecific T cell engagers (TCEs), has shown remarkable clinical activity, and several products have received market approval. However, despite promising results, most patients eventually become refractory and relapse, highlighting the need for alternative strategies. Engineered T cells secreting TCE antibodies (STAb) represent a promising strategy that combines the advantages of adoptive cell therapies and bispecific antibodies. Here, we undertook a comprehensive preclinical study comparing the therapeutic potential of T cells either expressing second-generation anti-BCMA CARs (CAR-T) or secreting BCMAxCD3 TCEs (STAb-T) in a T cell-limiting experimental setting mimicking the conditions found in patients with relapsed/refractory multiple myeloma. STAb-T cells recruited T cell activity at extremely low effector-to-target ratios and were resistant to inhibition mediated by soluble BCMA released from the cell surface, resulting in enhanced cytotoxic responses and prevention of immune escape of multiple myeloma cells in vitro. These advantages led to robust expansion and persistence of STAb-T cells in vivo, generating long-lived memory BCMA-specific responses that could control multiple myeloma progression in xenograft models, outperforming traditional CAR-T cells. These promising preclinical results encourage clinical testing of the BCMA-STAb-T cell approach in relapsed/refractory multiple myeloma.

Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de In

Author Info: (1) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (2) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. (3) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (4) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. (5) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. (6) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (7) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. (8) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (9) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (10) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (11) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), 28041 Madrid, Spain. (12) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (13) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (14) Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, 08036 Barcelona, Spain. (15) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (16) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. (17) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarc—n, 28223 Madrid, Spain. (18) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (19) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. (20) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (21) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), 28041 Madrid, Spain. (22) Centro de Biolog’a Molecular Severo Ochoa CSIC-UAM, 28049 Madrid, Spain. Instituto de Investigaci—n Sanitaria La Princesa, 28006 Madrid, Spain. (23) Centro de Biolog’a Molecular Severo Ochoa CSIC-UAM, 28049 Madrid, Spain. Instituto de Investigaci—n Sanitaria La Princesa, 28006 Madrid, Spain. (24) Molecular Immunology Unit, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, 28222 Madrid, Spain. (25) Department of Medicine, Medical School, Universidad Complutense de Madrid, 28040 Madrid, Spain. Department of Hematology, IML, IdISSC, Hospital Cl’nico San Carlos, 28040 Madrid, Spain. (26) H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 28029 Madrid, Spain. Department of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (27) H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 28029 Madrid, Spain. Department of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (28) Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Division of Hematopoietic Innovative Therapies, Biomedical Innovation Unit, Centro de Investigaciones EnergŽticas Medioambientales y Tecnol—gicas (CIEMAT), 28040 Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029 Madrid, Spain. Instituto de Investigaci—n Sanitaria Fundaci—n JimŽnez D’az, Universidad Aut—noma de Madrid (IIS-FJD, UAM), 28040 Madrid, Spain. (29) Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Institut d'Investigacions Biomdiques August Pi i Sunyer (IDIBAPS), Hospital Clinic de Barcelona, 08036 Barcelona, Spain. Servei d'Immunologia, Hospital Cl’nic de Barcelona, 08036 Barcelona, Spain. Plataforma Immunoterapia, Hospital Sant Joan de Deu, 08950 Barcelona, Spain. Universitat de Barcelona, 08007 Barcelona, Spain. (30) Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. H12O-CNIO Hematological Malignancies Clinical Research Unit, Spanish National Cancer Research (CNIO), 28029 Madrid, Spain. Department of Hematology, Hospital Universitario 12 de Octubre-Universidad Complutense, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. (31) Department of Immunology, Ophthalmology and ENT, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. Lymphocyte Immunobiology Group, Instituto de Investigaci—n Sanitaria 12 de Octubre (imas12), 28041 Madrid, Spain. (32) Department of Experimental Hematology, Instituto de Investigaci—n Sanitaria Fundaci—n JimŽnez Diaz, (IIS-FJD), Universidad Aut—noma de Madrid, 28040 Madrid, Spain. (33) Cancer Research Center (IBMCC, USAL-CSIC), Department of Medicine and Cytometry Service (NUCLEUS), Universidad de Salamanca, 37007 Salamanca, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Biomedical Research Institute of Salamanca (IBSAL), 37007 Salamanca, Spain. (34) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. Department of Biomedicine, School of Medicine, Universitat de Barcelona, 08007 Barcelona, Spain. Instituci— Catalana de Recerca i Estudis Avanats (ICREA), 08010 Barcelona, Spain. (35) Josep Carreras Leukaemia Research Institute, 08036 Barcelona, Spain. Red Espa–ola de Terapias Avanzadas (TERAV), Instituto de Salud Carlos III, 28029 Madrid, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Instituto de Salud Carlos III, 28029 Madrid, Spain. (36) Cancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain. Immuno-Oncology and Immunotherapy Group, Instituto de Investigaci—n Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, Spain. H12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Chair for Immunology UFV/Merck, Universidad Francisco de Vitoria (UFV), Pozuelo de Alarc—n, 28223 Madrid, Spain.

Immunogenic cell death in colorectal cancer: a review of mechanisms and clinical utility

Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality worldwide. Despite several clinical advances the survival of patients with advanced colorectal cancer remains limited, demanding newer approaches. The immune system plays a central role in cancer development, propagation, and treatment response. Within the bowel, the colorectal mucosa is a key barrier and site of immune regulation that is generally immunosuppressive. Nonetheless, within this tumour microenvironment, it is evident that anti-neoplastic treatments which cause direct cytotoxic and cytostatic effects may also induce immunogenic cell death (ICD), a form of regulated cell death that leads to an anti-tumour immune response. Therefore, novel ICD inducers and molecular biomarkers of ICD action are urgently needed to advance treatment options for advanced CRC. This article reviews our knowledge of ICD in CRC.

Author Info: (1) Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia. Department of Medical Oncology, Royal North Shore Ho

Author Info: (1) Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia. Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia. (2) Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia. (3) Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia. Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. (4) Department of Medical Oncology, Royal North Shore Hospital, St. Leonards, NSW, Australia. Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. (5) Bowel Cancer and Biomarker Research Laboratory, Kolling Institute, Royal North Shore Hospital, St Leonards, NSW, Australia. m.molloy@sydney.edu.au. Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. m.molloy@sydney.edu.au.

Cutting Edge: Phagosome-associated Autophagosomes Containing Antigens and Proteasomes Drive TAP-Independent Cross-Presentation

Activation of naive CD8-positive T lymphocytes is mediated by dendritic cells that cross-present MHC class I (MHC-I)-associated peptides derived from exogenous Ags. The most accepted mechanism involves the translocation of Ags from phagosomes or endolysosomes into the cytosol, where antigenic peptides generated by cytosolic proteasomes are delivered by the transporter associated with Ag processing (TAP) to the endoplasmic reticulum, or an endocytic Ag-loading compartment, where binding to MHC-I occurs. We have described an alternative pathway where cross-presentation is independent of TAP but remains dependent on proteasomes. We provided evidence that active proteasomes found within the lumen of phagosomes and endolysosomal vesicles locally generate antigenic peptides that can be directly loaded onto trafficking MHC-I molecules. However, the mechanism of active proteasome delivery to the endocytic compartments remained unknown. In this study, we demonstrate that phagosome-associated LC3A/B structures deliver proteasomes into subcellular compartments containing exogenous Ags and that autophagy drives TAP-independent, proteasome-dependent cross-presentation.

Author Info: (1) Department of Immunobiology, Yale School of Medicine, New Haven, CT. (2) Department of Immunobiology, Yale School of Medicine, New Haven, CT. (3) Department of Immunobiology, Y

Author Info: (1) Department of Immunobiology, Yale School of Medicine, New Haven, CT. (2) Department of Immunobiology, Yale School of Medicine, New Haven, CT. (3) Department of Immunobiology, Yale School of Medicine, New Haven, CT. Department of Dermatology, Yale School of Medicine, New Haven, CT. (4) Department of Cell Biology, Yale School of Medicine, New Haven, CT. (5) Department of Cell Biology, Yale School of Medicine, New Haven, CT. (6) Department of Immunobiology, Yale School of Medicine, New Haven, CT. (7) Department of Immunobiology, Yale School of Medicine, New Haven, CT. Department of Cell Biology, Yale School of Medicine, New Haven, CT.

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