PMID- 34049930 OWN - NLM STAT- MEDLINE DCOM- 20220105 LR - 20240226 IS - 2051-1426 (Electronic) IS - 2051-1426 (Linking) VI - 9 IP - 5 DP - 2021 May TI - In situ delivery of iPSC-derived dendritic cells with local radiotherapy generates systemic antitumor immunity and potentiates PD-L1 blockade in preclinical poorly immunogenic tumor models. LID - 10.1136/jitc-2021-002432 [doi] LID - e002432 AB - BACKGROUND: Dendritic cells (DCs) are a promising therapeutic target in cancer immunotherapy given their ability to prime antigen-specific T cells, and initiate antitumor immune response. A major obstacle for DC-based immunotherapy is the difficulty to obtain a sufficient number of functional DCs. Theoretically, this limitation can be overcome by using induced pluripotent stem cells (iPSCs); however, therapeutic strategies to engage iPSC-derived DCs (iPSC-DCs) into cancer immunotherapy remain to be elucidated. Accumulating evidence showing that induction of tumor-residing DCs enhances immunomodulatory effect of radiotherapy (RT) prompted us to investigate antitumor efficacy of combining intratumoral administration of iPSC-DCs with local RT. METHODS: Mouse iPSCs were differentiated to iPSC-DCs on OP9 stromal cells expressing the notch ligand delta-like 1 in the presence of granulocyte macrophage colony-stimulating factor. Phenotype and the capacities of iPSC-DCs to traffic tumor-draining lymph nodes (TdLNs) and prime antigen-specific T cells were evaluated by flow cytometry and imaging flow cytometry. Antitumor efficacy of intratumoral injection of iPSC-DCs and RT was tested in syngeneic orthotopic mouse tumor models resistant to anti-PD-1 ligand 1 (PD-L1) therapy. RESULTS: Mouse iPSC-DCs phenotypically resembled conventional type 2 DCs, and had a capacity to promote activation, proliferation and effector differentiation of antigen-specific CD8(+) T cells in the presence of the cognate antigen in vitro. Combination of in situ administration of iPSC-DCs and RT facilitated the priming of tumor-specific CD8(+) T cells, and synergistically delayed the growth of not only the treated tumor but also the distant non-irradiated tumors. Mechanistically, RT enhanced trafficking of intratumorally injected iPSC-DCs to the TdLN, upregulated CD40 expression, and increased the frequency of DC/CD8(+) T cell aggregates. Phenotypic analysis of tumor-infiltrating CD8(+) T cells and myeloid cells revealed an increase of stem-like Slamf6(+) TIM3(-) CD8(+) T cells and PD-L1 expression in tumor-associated macrophages and DCs. Consequently, combined therapy rendered poorly immunogenic tumors responsive to anti-PD-L1 therapy along with the development of tumor-specific immunological memory. CONCLUSIONS: Our findings illustrate the translational potential of iPSC-DCs, and identify the therapeutic efficacy of a combinatorial platform to engage them for overcoming resistance to anti-PD-L1 therapy in poorly immunogenic tumors. CI - (c) Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. FAU - Oba, Takaaki AU - Oba T AD - Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. AD - Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University, Matsumoto, Nagano, Japan. FAU - Makino, Kenichi AU - Makino K AD - Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. AD - Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan. FAU - Kajihara, Ryutaro AU - Kajihara R AD - Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. FAU - Yokoi, Toshihiro AU - Yokoi T AD - Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. FAU - Araki, Ryoko AU - Araki R AD - Department of Basic Medical Sciences for Radiation Damages, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. FAU - Abe, Masumi AU - Abe M AD - Department of Basic Medical Sciences for Radiation Damages, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. FAU - Minderman, Hans AU - Minderman H AD - Flow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. FAU - Chang, Alfred E AU - Chang AE AD - Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA. FAU - Odunsi, Kunle AU - Odunsi K AD - Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. AD - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. AD - Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. AD - University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA. FAU - Ito, Fumito AU - Ito F AUID- ORCID: 0000-0002-6866-671X AD - Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA fumito.ito@roswellpark.org. AD - Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. AD - Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. AD - Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, Nuew York, USA. LA - eng GR - K08 CA197966/CA/NCI NIH HHS/United States GR - P30 CA016056/CA/NCI NIH HHS/United States GR - R50 CA211108/CA/NCI NIH HHS/United States GR - U01 CA154967/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - J Immunother Cancer JT - Journal for immunotherapy of cancer JID - 101620585 RN - 0 (B7-H1 Antigen) RN - 0 (Cd274 protein, mouse) RN - 0 (Immune Checkpoint Inhibitors) SB - IM MH - Animals MH - B7-H1 Antigen/*antagonists & inhibitors/metabolism MH - CD8-Positive T-Lymphocytes/drug effects/immunology/metabolism MH - Cell Line, Tumor MH - Coculture Techniques MH - Dendritic Cells/immunology/metabolism/*transplantation MH - Immune Checkpoint Inhibitors/*pharmacology MH - *Immunotherapy, Adoptive MH - Induced Pluripotent Stem Cells/immunology/metabolism/*transplantation MH - Lymphocytes, Tumor-Infiltrating/drug effects/immunology/metabolism MH - Melanoma, Experimental/immunology/metabolism/pathology/*therapy MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Phenotype MH - Radiotherapy, Adjuvant MH - Signal Transduction MH - Skin Neoplasms/immunology/metabolism/pathology/*therapy MH - Tumor Burden/drug effects MH - Tumor Microenvironment MH - Mice PMC - PMC8166607 OTO - NOTNLM OT - adaptive immunity OT - dendritic cells OT - programmed cell death 1 receptor OT - radioimmunotherapy OT - vaccination COIS- Competing interests: AO was a co-founder of Tactiva Therapeutics and receives research support from AstraZeneca and Tessaro. EDAT- 2021/05/30 06:00 MHDA- 2022/01/06 06:00 PMCR- 2021/05/28 CRDT- 2021/05/29 05:40 PHST- 2021/04/23 00:00 [accepted] PHST- 2021/05/29 05:40 [entrez] PHST- 2021/05/30 06:00 [pubmed] PHST- 2022/01/06 06:00 [medline] PHST- 2021/05/28 00:00 [pmc-release] AID - jitc-2021-002432 [pii] AID - 10.1136/jitc-2021-002432 [doi] PST - ppublish SO - J Immunother Cancer. 2021 May;9(5):e002432. doi: 10.1136/jitc-2021-002432.