Evaluation of Immunomodulatory Agents in Classically Immunologically "Cold" Cancers Using Syngeneic Mouse Models of Breast and Ovarian Cancer

AACR 2018 -- T cell checkpoint inhibitors have demonstrated significant clinical benefit in immunologically "hot" cancer types like melanoma, kidney, bladder and lung cancers. "Hot" tumors are characterized by a significant CD8+ T cell infiltrate and high neoantigen burden. Breast cancer is regarded as an immunologically "cold" cancer, often with minimal CD8+ T cell infiltration and a much lower mutational burden. Preclinical researchers need robust and representative breast cancer models to test immuno-oncology (I-O) combination strategies that may convert these "cold" tumors into "hot" tumors. Radiation therapy (RT) is a clinical treatment modality utilized in breast cancer and is known to modify the tumor microenvironment, induce cytokines and chemokines, and has been shown to potentially synergize with immunotherapies. The 4T1 cell line is the most prevalent syngeneic breast cancer cell line model used in I-O research because of useful traits that include an immunosuppressed microenvironment with Tregs and G-MDSCs and highly metastatic phenotype. Mice with 4T1 tumors can develop a fatal hypersensitivity reaction upon repeated treatment with rat antibodies to PD-1, PD-L1, GITR or OX40. As alternative models for the study of immunologically "cold" breast cancers, we have characterized the tumor immune profiles of two breast cancer models, EMT6 and E0771; and the response of EMT6 and E0771 to radiation, costimulatory agonists and checkpoint inhibitors in pharmacology efficacy studies. Ovarian cancer is another cancer with low neoantigen burden and immunologically "cold". The response of intraperitoneal ID8 ovarian cancer model to checkpoint inhibitors has been characterized.