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Radiotherapy Cooperates with IL15 to Induce Antitumor Immune Responses.

ABSTRACT: Focal radiotherapy can promote cross-presentation of tumor antigens to T cells, but by itself, it is insufficient to induce therapeutically effective T-cell responses. The common gamma-chain cytokine IL15 promotes and sustains the proliferation and effector function of CD8⁺ T cells but has limited activity against poorly immunogenic tumors that do not elicit significant spontaneous T-cell responses. Here, we show that radiotherapy and subcutaneous IL15 had complementary effects and induced CD8⁺ T-cell-mediated tumor regression and long-term protective memory responses in two mouse carcinoma models unresponsive to IL15 alone. Mechanistically, radiotherapy-induced IFN type I production and Batf3-dependent conventional dendritic cells type 1 (cDC1) were required for priming of tumor-specific CD8⁺ T cells and for the therapeutic effect of the combination. IL15 cooperated with radiotherapy to activate and recruit cDC1s to the tumor. IL15 alone and in complex with a hybrid molecule containing the IL15? receptor have been tested in early-phase clinical trials in patients with cancer and demonstrated good tolerability, especially when given subcutaneously. Expansion of natural killer (NK) cells and CD8⁺ T cells was noted, without clear clinical activity, suggesting further testing of IL15 as a component of a combinatorial treatment with other agents. Our results provide the rationale for testing combinations of IL15 with radiotherapy in the clinic.

SUBMITTER: Pilones KA

PROVIDER: S-EPMC7415682 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Radiotherapy Cooperates with IL15 to Induce Antitumor Immune Responses.

Pilones Karsten A KA Charpentier Maud M Garcia-Martinez Elena E Daviaud Camille C Kraynak Jeffrey J Aryankalayil Joseph J Formenti Silvia C SC Demaria Sandra S

Cancer immunology research 20200612 8

Focal radiotherapy can promote cross-presentation of tumor antigens to T cells, but by itself, it is insufficient to induce therapeutically effective T-cell responses. The common gamma-chain cytokine IL15 promotes and sustains the proliferation and effector function of CD8<sup>+</sup> T cells but has limited activity against poorly immunogenic tumors that do not elicit significant spontaneous T-cell responses. Here, we show that radiotherapy and subcutaneous IL15 had complementary effects and in ...[more]

PMID: 32532811

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Project description:ObjectiveTo develop a neoantigen-targeted personalized cancer treatment for non-small cell lung cancer (NSCLC), neoantigens were obtained from collected human lung cancer samples, and the utility of neoantigen and neoantigen-reactive T cells (NRTs) was assessed.MethodsTumor specimens from three patients with NSCLC were obtained and analyzed by whole-exome sequencing, and neoantigens were predicted accordingly. Dendritic cells and T lymphocytes were isolated, NRTs were elicited and IFN-γ ELISPOT tests were conducted. HLA-A2.1/Kb transgenic mice were immunized with peptides from HLA-A*02:01+patient with high immunogenicity, and NRTs were subjected to IFN-γ, IL-2 and TNF-α ELISPOT as well as time-resolved fluorescence assay for cytotoxicity assays to verify the immunogenicity in vitro. The HLA-A*02:01+lung cancer cell line was transfected with minigene and inoculated into the flanks of C57BL/6nu/nu mice and the NRTs induced by the immunogenic polypeptides from autologous HLA-A2.1/Kb transgenic mice were adoptively transfused to verify their immunogenicity in vivo.ResultsMultiple putative mutation-associated neoantigens with strong affinity for HLA were selected from each patient. Immunogenic neoantigen were identified in all three NSCLC patients, the potency of ACAD8-T105I, BCAR1-G23V and PLCG1-M425L as effective neoantigen to active T cells in suppressing tumor growth was further proven both in vitro and in vivo using HLA-A2.1/Kb transgenic mice and tumor-bearing mouse models.ConclusionNeoantigens with strong immunogenicity can be screened from NSCLC patients through the whole-exome sequencing of patient specimens and machine-learning-based neoantigen predictions. NRTs shown efficient antitumor responses in transgenic mice and tumor-bearing mouse models. Our results indicate that the development of neoantigen-based personalized immunotherapies in NSCLC is possible.PrecisNeoantigens with strong immunogenicity were screened from NSCLC patients. This research provides evidence suggesting that neoantigen-based therapy might serve as feasible treatment for NSCLC.

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Radiotherapy Cooperates with IL15 to Induce Antitumor Immune Responses.

Publications

Radiotherapy Cooperates with IL15 to Induce Antitumor Immune Responses.

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