Kornelia Polyak

Insights into immune escape during tumor evolution and response to immunotherapy using a rat model of breast cancer

Kornelia Polyak, MD PhD
Professor of Medicine
Harvard Medical School
Department of Medical Oncology
Dana-Farber Cancer Institute
Boston, MA, USA

This conference is organized by Jean-François Coté. It is part of the 2021-2022 IRCM conference calendar. Due to the COVID-19 pandemic, the conference series will be presented on Zoom.

Zoom Link : https://zoom.us/j/95269762104
ID : 952 6976 2104
Code : 476372

About the conference:
Breast cancer progression from DCIS, to IDC, to metastasis presents an increasingly immunosuppressive environment characterized by lower anti-tumor cytotoxic CD8+ T cell activation and higher immunosuppressive Treg recruitment. Although genomic changes such as CD274 amplification encoding PD-L1 contribute to immunosuppressive microenvironment, this is not the sole mechanism of immune evasion. Therefore there is a need to develop other approaches of preventing or restoring CD8+ T cell dysfunction. We hypothesize that a progressively suppressive immune microenvironment is critical for in situ to invasive transition in both breast and pancreatic cancer, and that by re-activating immune responses initiation and progression may be prevented or delayed. In order to test this hypothesis, we monitored tumor incidence and growth in response to treatment with immune modulators using a novel, immunogenic, carcinogen-induced rat model. Like human tumors, carcinogen-induced tumors 1) show a similar progression from DCIS to IDC, 2) recapitulate human tumor subtypes such as basal, luminal, and HER2+, 3) are immunogenic and have robust recruitment of T and B lymphocytes as well as macrophages and neutrophils, 4) have similar spatial localization of T cells, and 5) anti-tumor CD8+ activation decreases as the tumors progress. Using this model we tested a TGFβ receptor inhibitor (TGFβRi), in order to increase immune responses, as TGFβ inhibits naïve T cell proliferation, natural killer and CD8+ T cell effector function and induces suppressive Tregs and myeloid derived suppressor cells (MDSCs). We treated the rats with TGFβRi and PD-L1 alone or in combination either before or after tumors arose, to look at both prevention of initiation and progression, respectively. TGFβ inhibition alone or in combination with PD-L1 blockade led to a decrease in carcinogen-induced tumor incidence and had an effect in tumor growth, suggesting that anti-tumor T cell responses might already be in place but are repressed early in tumorigenesis. We find that tumors’ responses can vary widely to TGFβ inhibition or PD-L1 blockade with clear responders and escapers. Tumors that were stable or regressing (regardless of their treatment), had higher CD45+ leukocyte infiltration compared to tumors that were growing, where leukocytes localized mostly to depositions of collagen, as seen in fibrosis, surrounding the tumor. Interestingly, responder tumors had a higher number of activated cells when compared to escapers. These results suggest that for effective immunotherapies, both activation and recruitment of anti-tumor T cells would need to be modulated and therefore combination treatments with ECM modulators are warranted.

About Kornelia Polyak:
Dr. Kornelia Polyak is a professor of Medicine at the Dana-Farber (DF) Cancer Institute at Harvard Medical School, in Boston, MA, USA, and co-leader of the Cancer Cell Biology Program of the DF/Harvard Cancer Center (HCC). As a physician-scientist, she is involved in biomedical research centered on patient care and dedicated to understanding how breast tumors evolve. Dr. Polyak maintains active collaborations with research teams around the world, from France to Japan, and has authored more than 150 manuscripts in peer-reviewed, high-impact journals such as Cancer Cell, Nature, etc.  

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