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Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated murine 4T1 TNBC tumors

ABSTRACT: Immune therapy has emerged as the new frontier of cancer treatment. Therapeutic radiation is a known inducer of an immune response that can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2), which is highly expressed in triple negative breast tumors. A clinical cohort of triple negative breast cancer (TNBC) tumors revealed that elevated COX2 tumor expression predicted poor radiation therapeutic efficacy. Using the aggressive murine 4T1 TNBC model, we show that treatment with ionizing radiation and adjuvant NSAID (indomethacin) therapy to inhibit COX2 provides a powerful combination to reduce both primary tumor growth and lung metastasis through immune modulation. Using whole tumor RNAseq and multiplex fluorescence imaging, this study reveals spatial immunological changes in the treated primary tumor. Indomethacin alone increased the infiltration of lymphoid populations into the primary tumor. Importantly, the combined treatment improved lymphoid infiltration into the tumor epithelium, augmented cGAS/STING1 and type I IFN gene expression and altered key immune checkpoints including PD1, IDO, and CTLA4. Markedly increased B cell and T cell populations with increased CD8+ T cell activation and reduced T cell exhaustion were observed. Thus, adjuvant NSAID treatment combined with radiation therapy shifts “immune desert phenotypes” toward anti-tumor immune mediators favoring M1/Th1 signatures in the immunologically challenging 4T1 tumor model. Importantly, radiation/indomethacin combination improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared to mice treated with single agent radiation. These results show that clinically available NSAID’s augment radiation therapeutic efficacy through improved antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs

ORGANISM(S): Mus musculus

PROVIDER: GSE264712 | GEO | 2024/05/28

REPOSITORIES: GEO

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Project description:Accumulating data support the concept that ionizing radiation therapy (RT) has the potential to convert the tumor into an in situ, individualized vaccine; however this potential is rarely realized by RT alone. Transforming growth factor β (TGFβ) is an immunosuppressive cytokine that is activated by RT and inhibits the antigen-presenting function of dendritic cells and the differentiation of effector CD8+ T cells. Here we tested the hypothesis that TGFβ hinders the ability of RT to promote anti-tumor immunity. Development of tumor-specific immunity was examined in a pre-clinical model of metastatic breast cancer. Mice bearing established 4T1 mouse mammary carcinoma treated with pan-isoform specific TGFβ neutralizing antibody, 1D11, showed significantly improved control of the irradiated tumor and non-irradiated metastases, but no effect in the absence of RT. Notably, whole tumor transcriptional analysis demonstrated the selective upregulation of genes associated with immune-mediated rejection only in tumors of mice treated with RT+TGFβ blockade. Mice treated with RT+TGFβ blockade exhibited cross-priming of CD8+ T cells producing IFNγ in response to three tumor-specific antigens in tumor-draining lymph nodes, which was not evident for single modality treatment. Analysis of the immune infiltrate in mouse tumors showed a significant increase in CD4+ and CD8+ T cells only in mice treated with the combination of RT+TGFβ blockade. Depletion of CD4+ or CD8+ T cells abrogated the therapeutic benefit of RT+TGFβ blockade. These data identify TGFβ as a master inhibitor of the ability of RT to generate an in situ tumor vaccine, which supports testing inhibition of TGFβ during radiotherapy to promote therapeutically effective anti-tumor immunity. We used genome-wide microarray to depict main biological processes responsibles for the therapeutic benefit of the combination ofTGF-beta blockade and local radiotherapy. To gain a more comprehensice protrait of the effects of RT and TGFbeta blockade on gene expressionin tumors, we collected 4T1 tumors 4 days after completion of RT. Three tumors from each group were then subjected to RNA extraction and hybridization on affymetrix array.

Project description:Radiation and BCG instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response however comparison of STING-pathway molecules and immune landscape following treatment in urothelial carcinoma has not be performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15Gy dose of radiation or 3 intravesical instillations of BCG (1x108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation.

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Adjuvant COX inhibition augments STING signaling and cytolytic T cell infiltration in irradiated murine 4T1 TNBC tumors

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