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Enhanced antitumor immunity through sequential targeting of PI3K? and LAG3.

ABSTRACT: BACKGROUND:Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3K? signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. METHODS:Mice bearing 4T1 mammary tumors were orally administered a PI3K? inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3K? inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. RESULTS:As observed in human immunotherapy trials with other agents, immunomodulation by PI3K?-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8+ T cells, T cell factor 1 (TCF1)+ T cells and CD69- T cells, compatible with induction of a sustained tumor-specific T cell response. Treg numbers were significantly reduced in both regressor and non-regressor tumors compared with untreated tumors. The remaining Treg in non-regressor tumors were however significantly enriched with cells expressing the coinhibitory receptor LAG3, compared with Treg in regressor and untreated tumors. This striking difference prompted us to sequentially block PI3K? and LAG3. This combination enabled successful therapy of all mice, demonstrating the functional importance of LAG3 in non-regression of tumors on PI3K? inhibition therapy. Follow-up studies, performed using additional cancer cell lines, namely MC38 and CT26, indicated that a partial initial response to PI3K? inhibition is an essential prerequisite to a sequential therapeutic benefit of anti-LAG3 antibodies. CONCLUSIONS:These data indicate that LAG3 is a key bottleneck to successful PI3K?-targeted immunotherapy and provide a rationale for combining PI3K?/LAG3 blockade in future clinical studies.

SUBMITTER: Lauder SN

PROVIDER: S-EPMC7583804 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3.

Lauder Sarah Nicol SN Smart Kathryn K Kersemans Veerle V Allen Danny D Scott Jake J Pires Ana A Milutinovic Stefan S Somerville Michelle M Smart Sean S Kinchesh Paul P Lopez-Guadamillas Elena E Hughes Ellyn E Jones Emma E Scurr Martin M Godkin Andrew A Friedman Lori S LS Vanhaesebroeck Bart B Gallimore Awen A

Journal for immunotherapy of cancer 20201001 2

<h4>Background</h4>Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors.<h4>Methods</h4>Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growt ...[more]

PMID: 33093155

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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.

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Enhanced antitumor immunity through sequential targeting of PI3K? and LAG3.

Publications

Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3.

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