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Macrophage Syk-PI3K? Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression.

ABSTRACT: Macrophages (M?) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in M?s that promote tumor immunosuppression will provide therapeutic benefit. PI3K? has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an M? Syk-PI3K axis drives polarization of immunosuppressive M?s that establish an immunosuppressive tumor microenvironment in in vivo syngeneic tumor models. Genetic or pharmacologic inhibition of Syk and/or PI3K? in M?s promotes a proinflammatory M? phenotype, restores CD8+ T-cell activity, destabilizes HIF under hypoxia, and stimulates an antitumor immune response. Assay for transposase-accessible Chromatin using Sequencing (ATAC-seq) analyses on the bone marrow-derived macrophages (BMDM) show that inhibition of Syk kinase promotes activation and binding of NF-?B motif in SykMC-KO BMDMs, thus stimulating immunostimulatory transcriptional programming in M?s to suppress tumor growth. Finally, we have developed in silico the "first-in-class" dual Syk/PI3K inhibitor, SRX3207, for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.

SUBMITTER: Joshi S

PROVIDER: S-EPMC7450492 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Macrophage Syk-PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression.

Joshi Shweta S Liu Kevin X KX Zulcic Muamera M Singh Alok R AR Skola Dylan D Glass Christopher K CK Sanders P Dominick PD Sharabi Andrew B AB Pham Timothy V TV Tamayo Pablo P Shiang Daniel D Dinh Huy Q HQ Hedrick Catherine C CC Morales Guillermo A GA Garlich Joseph R JR Durden Donald L DL

Molecular cancer therapeutics 20200123 3

Macrophages (MΦ) play a critical role in tumor growth, immunosuppression, and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we report that an MΦ Syk-PI3K axis drives polarization of immunosuppressive MΦs that establish an immunosuppressive tumor microenvironment in <i>in vivo</ ...[more]

PMID: 31974273

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Project description: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.

Dataset Information

Macrophage Syk-PI3K? Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression.

Publications

Macrophage Syk-PI3Kγ Inhibits Antitumor Immunity: SRX3207, a Novel Dual Syk-PI3K Inhibitory Chemotype Relieves Tumor Immunosuppression.

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