論文 - 詳細
| RRC ID | 72500 |
|---|---|
| 著者 | Oba T, Makino K, Kajihara R, Yokoi T, Araki R, Abe M, Minderman H, Chang AE, Odunsi K, Ito F. |
| タイトル | 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. |
| ジャーナル | J Immunother Cancer |
| Abstract |
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. |
| 巻・号 | 9(5) |
| 公開日 | 2021-5-1 |
| DOI | 10.1136/jitc-2021-002432 |
| PII | jitc-2021-002432 |
| PMID | 34049930 |
| PMC | PMC8166607 |
| MeSH | Animals B7-H1 Antigen / antagonists & inhibitors* B7-H1 Antigen / metabolism CD8-Positive T-Lymphocytes / drug effects CD8-Positive T-Lymphocytes / immunology CD8-Positive T-Lymphocytes / metabolism Cell Line, Tumor Coculture Techniques Dendritic Cells / immunology Dendritic Cells / metabolism Dendritic Cells / transplantation* Immune Checkpoint Inhibitors / pharmacology* Immunotherapy, Adoptive* Induced Pluripotent Stem Cells / immunology Induced Pluripotent Stem Cells / metabolism Induced Pluripotent Stem Cells / transplantation* Lymphocytes, Tumor-Infiltrating / drug effects Lymphocytes, Tumor-Infiltrating / immunology Lymphocytes, Tumor-Infiltrating / metabolism Melanoma, Experimental / immunology Melanoma, Experimental / metabolism Melanoma, Experimental / pathology Melanoma, Experimental / therapy* Mice, Inbred C57BL Mice, Transgenic Phenotype Radiotherapy, Adjuvant Signal Transduction Skin Neoplasms / immunology Skin Neoplasms / metabolism Skin Neoplasms / pathology Skin Neoplasms / therapy* Tumor Burden / drug effects Tumor Microenvironment |
| IF | 10.252 |
| リソース情報 | |
| ヒト・動物細胞 | OP9(RCB1124) OP9/G-DLL1(RCB2925) |