The development of adaptive immune checkpoint inhibitors, which prevent tumor-mediated inactivation of lymphocytes, has drastically improved outcomes for advanced cancer patients. However, only 20-30% of patients benefit from these treatments and those that do often present moderate toxicity and/or later relapse. After discovering a novel innate immune checkpoint, we have identified a therapeutic strategy to restore the tumor-suppressed immune response during chemotherapy. Here, we show that multiple tumor types (including melanoma, lung, breast and pancreatic cancers) co-cultured with murine primary macrophages suppress the expression of the essential Toll-like Receptor (TLR) signal-transducing adapter protein MyD88 by 57-81% +/- 2-5% (mean +/- SEM). In the absence of MyD88, macrophages are unable to respond to TLR stimulating Damage Associated Molecular Patterns (DAMPs) released by dying tumor cells after chemotherapy, leading to as much as 97% +/- 6% reduction in pro-inflammatory gene expression in our co-culture models. Tumors exert this suppression by activating the macrophage Mer receptor, inducing recruitment of a phosphatase, known as PTP1b, and Stat1 to Mer. Increasing association between PTP1b and Stat1 leads to reduced Stat1 phosphorylation and translocation to the nucleus as well as a downstream reduction in MyD88 expression. Treatment with a pharmacological inhibitor of PTP1b (BVT948) blocks the association of Mer, PTP1b and Stat1, restoring MyD88 expression and responsiveness to chemotherapy-released DAMPs. In chemotherapy-resistant murine syngeneic melanoma models, including B16F10 and GEMM6 (Braf V600E, Pten-/-), we show that combination therapy with BVT948 and Cisplatin or Vemurafenib, respectively, leads to a 47% reduction in tumor growth rates. Treating chemo- and immuno-therapy resistant Lewis Lung Cancer (LLC) tumor-bearing mice with combination BVT948/Cisplatin therapy leads to a similar reduction in tumor growth that is magnified with the addition of adaptive immune checkpoint blockade. In summary, we have described a novel mechanism of cancer-mediated immune suppression that dramatically reduces the immune response during chemotherapy. PTP1b inhibition could represent a novel therapeutic strategy to improve the effectiveness of conventional chemotherapy in patients with advanced malignancies.

Citation Format: Nestor Prieto-Dominguez, Eric S. Ubil. Restoring the tumor-suppressed immune response during chemotherapy by targeting Mer:PTP1b interactions [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO018.