Oba and Makino et al. generated iPSC-derived cDC2s. In syngeneic orthotopic mouse models of immunologically cold melanoma and breast cancer, intratumoral iPSC-DC injection + tumor irradiation (RT) synergized to delay growth of directly treated and, in a bilateral model, distal tumors. RT induced tumor-injected iPSC-DCs to migrate to tumor-draining lymph nodes, express CD40, and aggregate with other DCs and CD8+ T cells. RT + iPSC-DC tumor injection increased tumor-specific Slamf6+PD-1int exhausted progenitor CD8+ T cells, increased PD-L1 on TAMs and DCs in tumors, induced tumor-specific immune memory, and enhanced the efficacy of PD-L1 blockade.
Contributed by Paula Hochman
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.
Author Info: (1) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University,
Author Info: (1) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Division of Breast and Endocrine Surgery, Department of Surgery, Shinshu University, Matsumoto, Nagano, Japan. (2) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Department of Obstetrics and Gynecology, Akita University Graduate School of Medicine, Akita, Japan. (3) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. (4) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. (5) Department of Basic Medical Sciences for Radiation Damages, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. (6) Department of Basic Medical Sciences for Radiation Damages, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan. (7) Flow & Image Cytometry Shared Resource, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. (8) Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA. (9) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. University of Chicago Medicine Comprehensive Cancer Center, Chicago, Illinois, USA. (10) Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA fumito.ito@roswellpark.org. Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA. Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, Nuew York, USA.
