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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:Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a ?30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3? and inhibition of GSK3?, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death - at least in part - by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.

Dataset Information

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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