Abstract 5691: Evaluation of immunomodulatory agents in classically immunologically 'cold' cancers using syngeneic mouse models of breast and ovarian cancer
Authors: Daniel Dylan , Urs Sumithra , Guley Kevin , Krueger Sarah , Draper David , Wong Alden , Evens Hillary , Higginbottom Claire , Saims Dan , Wise Scott , Franklin Maryland Rosenfeld 
Published: August 2018

The clinical successes of immunotherapy in immunologically “hot” cancers such as kidney, bladder and lung cancers has lead researchers to pursue strategies to improve the initiation of immune responses in immunologically more “cold” cancers such as breast and ovarian cancer. We have characterized two syngeneic mouse models of breast cancer, 4T1 and E0771, and an ovarian cancer model, ID8, for their baseline immune profile and responsiveness to various immunotherapy approaches in an effort to enable rational combination therapy.

The 4T1 model has useful traits for immuno-oncology research including a highly metastatic phenotype. However, our data illustrate that the tumors have a paucity of CD8 T cells and a highly immunosuppressed microenvironment with Tregs and ~80% G-MDSCs of CD11b+ cells leading to primary resistance to checkpoint blockade. Radiation can induce changes in an immunosuppressive microenvironment and radiotherapy remains an important clinical modality for the treatment of breast cancer. Treatment of 4T1 tumors with radiation resulted in a ~15% reduction of total MDSCs in the mice receiving 8Gy daily for three days. For the purpose of guiding future immunotherapy combinations, we established a focal beam radiation dose response and found single dose 5Gy had no activity while 10 or 20Gy resulted in increasing anti-tumor effects.

The baseline immune cell profiling for E0771, a triple negative breast cancer, revealed notable differences to 4T1. While both models have a similar proportion of CD4 T cells and Tregs, 4T1 has ~55% G-MDSCs of CD11b+ cells while E0771 has ~0.4%. The content of M-MDSCs is nearly reciprocal with E0771 having ~49% M-MDSCs of CD11b+ cells and 4T1 having ~7%. The E0771 model also has a higher proportion of CD8 T cells than 4T1. Based on its immune profile, E0771could be a better candidate for responding to checkpoint inhibition. An efficacy study in the E0771 model demonstrated high sensitivity to inhibitors of PD-1, PD-L1, and CTLA-4, although the activity of anti-PD-1 on established tumors was more modest. Costimulatory agonistic antibodies to OX40, CD137 and GITR were also highly active. These data suggest that E0771 may represent a more immunologically “warm” breast cancer.

We have developed the ID8-Luc-mCh-Puro syngeneic mouse cell line as an orthotopic (intraperitoneal) model of ovarian cancer wherein tumor burden is monitored by bioluminescence imaging. Immune profiling on ascites from ID8-Luc-mCh-Puro bearing mice shows heterogeneity in the profiles between mice; although, all mice have robust CD8+ T cell infiltration with favorable CD8+ T cell/Treg ratios. The activity of checkpoint inhibitors against orthotopic ID8-Luc-mCh-Puro is currently being evaluated. Together, these models of breast and ovarian cancer can be used to evaluate anti-tumor immune responses in immunologically more quiescent indications.

Citation Format: Dylan Daniel, Sumithra Urs, Kevin Guley, Sarah Krueger, David Draper, Alden Wong, Hillary Evens, Claire Higginbottom, Dan Saims, Scott Wise, Maryland Rosenfeld Franklin. Evaluation of immunomodulatory agents in classically immunologically 'cold' cancers using syngeneic mouse models of breast and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5691.