Abstract B13: Immune cells, tumor-initiating cells, and drug sensitivity in claudin-low TNBC: A delicate balance

Abstract

Abstract Background: Breast cancer is a heterogeneous disease. Based on gene expression profiling, it can be classified into at least 5 subtypes. They are luminal A and B, normal breast-like, Her2-positive, basal-like, and newly described claudin-low. Among all these subtypes, basal-like and claudin-low tumors have relatively poor prognosis. Claudin-low tumors are characterized by the low expression of cell-cell junction proteins like claudin 3 and E-cadherin along with an enrichment of EMT markers such as SNAI1 and SNAI2 and high levels of mesenchymal markers such as vimentin. Claudin-low tumors are generally more aggressive and the rate of response to primary chemotherapy is around 32%. Initial data have shown that p-53 null claudin-low tumors are sensitive to cyclophosphamide treatment. Cyclophosphamide (CTX) is a chemotherapy drug that has been used in lymphoma, leukemia and some solid tumors. At low and continuous doses, it shows immunostimulatory properties. The overall goal of this proposal is to test the therapeutic response of claudin-low tumors to cyclophosphamide treatment and define the functional role of the immune system in a mouse model of claudin-low breast cancer. Preliminary data have shown that tumor cells in a p53 null claudin-low murine model (T12) possess tumor-initiating abilities and have STAT3 activation. Initial data in claudin-low T12 tumors also suggest that CTX induces CD4+ and CD8+ T-cell homing to the primary tumor. Additionally, wild-type Balb/c mice implanted with T12 tumors respond favorably to CTX treatment as compared to T cell-deficient NSG mice. Our studies have shown that treatment-resistant claudin-low tumors have a high tumor-associated macrophage (TAM) infiltrate. Tumors with poor response to CTX show higher levels of vimentin staining as compared to responsive tumors. Depletion of specific T-cell subsets to determine their functional importance in the response to CTX shows that while CD8+ T-cell depletion does not have a significant effect on treatment response, depletion of CD4+ T cells results in impaired tumor response to CTX treatment. Additionally, TAMs increase upon CD4+ T-cell depletion. We hypothesize that CTX treatment can sensitize T12 primary tumors to CD4+ T-cell mediated apoptosis. We further hypothesize that TAMS can suppress T-cell function and this, along with changes in the tumor EMT status, can promote chemoresistance. TAMs can also interact with tumor-initiating cells (TIC) within claudin-low tumors via the STAT3 pathway to promote survival and proliferation of chemotherapy resistant TICs. Furthermore, depleting immunosuppressive cells such as TAMs may provide us with an additional therapeutic modality for chemotherapy-resistant breast cancer in combination with checkpoint immunotherapy. Reference: 1. Prat A et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res 2010;12:R68. Citation Format: Swarnima Singh, Se-Jin Kim, Xiang Zhang, Jeffrey Rosen. Immune cells, tumor-initiating cells, and drug sensitivity in claudin-low TNBC: A delicate balance [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr B13.