Abstract PR010: Potentiating the efficacy of immune checkpoint blockade by targeting the epithelial-to-mesenchymal transition (EMT) in breast carcinomas

Abstract

Abstract The epithelial-to-mesenchymal transition (EMT), which conveys epithelial (E) carcinoma cells to quasi-mesenchymal (qM) states, enables these cells to gain tumor-initiating stem like abilities, metastasize and acquire resistance to several drug and chemotherapeutic regimens. In addition to these aforementioned features, we have recently demonstrated that the EMT program also contributes to the generation of an immunosuppressive tumor microenvironment (TME) in breast carcinomas and confers resistance to immune checkpoint blockade therapies. Specifically, qM tumors recruit immunosuppressive cells to their TME and are refractory to checkpoint blockade, while E tumors recruit CD8+ T-cells instead and are sensitive to checkpoint blockade. Importantly, minority populations of qM cells within a tumor can cross-protect their more E neighbors from immune attack. The underlying mechanisms by which this immunosuppression and cross-protection are achieved have been unclear. Using a combination of novel E and qM tumor models arising in syngeneic immunocompetent hosts combined with CRISPR/Cas9 and transcriptomic approaches, we demonstrate that qM but not E tumors are specifically associated with an immunosuppressive gene signature. Furthermore, abrogation of carcinoma cell-derived factors (CD73, Csf1 or Spp1) specifically associated with the qM state, prevents the assembly of an immunosuppressive TME and sensitizes otherwise refractory qM tumors partially or completely to checkpoint blockade immunotherapy. Taken together, our work indicates that carcinoma cell-intrinsic factors specifically associated with residence in the qM state can directly influence their response to anti-tumor immunity and checkpoint blockade. As a result, this work brings to the forefront the possibility of using the epithelial-mesenchymal state of carcinoma cells as an important surrogate marker that can be used to predict responses to immune checkpoint blockade therapies. This abstract is also being presented as PO038. Citation Format: Anushka Dongre, Mohammad Rashidian, Elinor Ng Eaton, Ferenc Reinhardt, Prat Thiru, Maria Zagorulya, Sunita Nepal, Tuba Banaz, Anna Martner, Stefani Spranger, Robert A. Weinberg. Potentiating the efficacy of immune checkpoint blockade by targeting the epithelial-to-mesenchymal transition (EMT) in breast carcinomas [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 PR010.