AACR Annual Meeting
“Evaluation of Immunomodulatory Agents in Classically Immunologically “Cold” Cancers Using Syngeneic Mouse Models of Breast and Ovarian Cancer“
Introduction and Background
- 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.