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Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7R? Dependent.

ABSTRACT: Adoptive cellular therapy, in which activated tumor-reactive T cells are transferred into lymphodepleted recipients, is a promising cancer treatment option. Activation of T cells decreases IL7 responsiveness; therefore, IL15 is generally considered the main driver of effector T-cell responses in this setting. However, we found in lymphodepleted mice that CD8(+) T cells activated with IL12 showed enhanced engraftment that was initially dependent on host IL7, but not IL15. Mechanistically, enhanced IL7 responsiveness was conferred by elevated IL7R? expression, which was critical for antitumor immunity. Elevated IL7R? expression was achievable without IL12, as polyclonal CD8(+) T cells activated with high T-cell receptor (TCR) stimulation depended on T-cell IL7R? expression and host IL7 for maximal engraftment. Finally, IL12 conditioning during the activation of human CD8(+) T cells, including TCR-modified T cells generated using a clinically relevant protocol, led to enhanced IL7R? expression. Our results demonstrate the importance of the donor IL7R?/host IL7 axis for effector CD8(+) T-cell engraftment and suggest novel strategies to improve adoptive cellular therapy as a cancer treatment.

SUBMITTER: Johnson CB

PROVIDER: S-EPMC4766846 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent.

Johnson C Bryce CB Riesenberg Brian P BP May Bennett R BR Gilreath Stuart C SC Li Guangfu G Staveley-O'Carroll Kevin F KF Garrett-Mayer Elizabeth E Mehrotra Shikhar S Cole David J DJ Rubinstein Mark P MP

Cancer immunology research 20150821 12

Adoptive cellular therapy, in which activated tumor-reactive T cells are transferred into lymphodepleted recipients, is a promising cancer treatment option. Activation of T cells decreases IL7 responsiveness; therefore, IL15 is generally considered the main driver of effector T-cell responses in this setting. However, we found in lymphodepleted mice that CD8(+) T cells activated with IL12 showed enhanced engraftment that was initially dependent on host IL7, but not IL15. Mechanistically, enhance ...[more]

PMID: 26297711

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Project description:BackgroundRadiotherapy enhances antitumor immunity. However, it also induces immunosuppressive responses, which are major hurdles for an effective treatment. Thus, targeting the immunosuppressive tumor microenvironment is essential for enhancing the antitumor immunity after radiotherapy. Retrospective studies show that a blockade of PI3Kδ and/or γ, which are abundant in leukocytes, exhibits antitumor immune response by attenuating activity of immune suppressive cells, however, the single blockade of PI3Kδ or γ is not sufficient to completely eliminate solid tumor.MethodsWe used BR101801, PI3Kδ/γ inhibitor in the CT-26 syngeneic mouse model with a subcutaneously implanted tumor. BR101801 was administered daily, and the target tumor site was locally irradiated. We monitored the tumor growth regularly and evaluated the immunological changes using flow cytometry, ELISpot, and transcriptional analysis.ResultsThis study showed that BR101801 combined with irradiation promotes systemic antitumor immunity and abscopal response by attenuating the activity of immune suppressive cells in the CT-26 tumor model. BR101801 combined with irradiation systemically reduced the proliferation of regulatory T cells (Tregs) and enhanced the number of tumor-specific CD8α+ T cells in the tumor microenvironment, thereby leading to tumor regression. Furthermore, the high ratio of CD8α+ T cells to Tregs was maintained for 14 days after irradiation, resulting in remote tumor regression in metastatic lesions, the so-called abscopal effect. Moreover, our transcriptomic analysis showed that BR101801 combined with irradiation promoted the immune-stimulatory tumor microenvironment, suggesting that the combined therapy converts immunologically cold tumors into hot one.ConclusionsOur data suggest the first evidence that PI3Kδ/γ inhibition combined with irradiation promotes systemic antitumor immunity against solid tumors, providing the preclinical result of the potential use of PI3Kδ/γ inhibitor as an immune-regulatory radiosensitizer.

Dataset Information

Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7R? Dependent.

Publications

Effector CD8+ T-cell Engraftment and Antitumor Immunity in Lymphodepleted Hosts Is IL7Rα Dependent.

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