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Job Title
Postdoctoral Fellow
Academic Rank
Fellow or Postdoc
Department
Surgery
Authors
Adam Nelson, Anita K. Mehta, Madeline Townsend, Madisson Oliwa, Kelly F. Zheng, Filipa Lynce, Nabihah Tayob, Geoffrey I. Shapiro, and Jennifer L. Guerriero
Principal Investigator
Dr. Jennifer Guerriero
Categories
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Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) have improved outcomes of BRCA-associated breast cancer; however, treatment responses are often not durable. We recently showed that PARPi induce CSF-1R+ suppressive tumor-associated macrophages (TAMs) that restrict anti-tumor immune responses, contributing to PARPi resistance, indicating targeting TAMs may improve PARPi therapy.
Methods: Mice bearing Brca1-deficient TNBC tumors were treated with PARPi (talazoparib) ± small molecule inhibitor of CSF-1R (ARRAY-382; CSF-1Ri) ± anti-PD-1 and followed for survival. Flow cytometry and Nanostring gene expression analysis were employed to elucidate changes in the TME following short-term treatment.
Results: PARPi+Arry-382-treated mice had superior tumor clearance compared to PARPi monotherapy. Triple combination of anti-PD-1 + PARPi + CSF-1Ri demonstrated similar clearance of tumor by day 98 compared to PARPi+CSF-1Ri, However, triple combination led to superior long-term tumor clearance. Flow cytometry revealed an increasing trend of infiltrating Granzyme B+CD8+T-cells in triple therapy-treated tumors, compared to PARPi+CSF-1Ri-treated tumors. Triple therapy-treated tumors had increased expression of genes associated with anti-tumor immune response, antigen presentation, and T-cell chemotaxis compared to PARPi+CSF-1Ri.
Conclusion: These data confirm targeting TAMs induces anti-tumor responses that enhance PARPi therapy, which can be further enhanced by ICB, resulting in further favorable modulation of the TME.
Breast cancer is the most common and the second leading cause of cancer death in women. Current treatments for breast cancer, including chemotherapies, can have harsh side effects, that can cause patients to stop treatment. Therefore, new treatments that are safe, and effective are desperately needed. Poly-ADP ribose polymerase (PARP) inhibitors (PARPi) have emerged as a promising treatment for cancers with defects in the breast cancer gene (BRCA), however patients eventually stop responding to therapy. Previously, our lab has shown that PARPi increases the recruitment of a type of immune cell called macrophages which promote tumor growth and limit patient response to cancer treatment. Therefore, targeting macrophages may improve PARPi treatment. Using a small molecule (ARRY-382) targeting macrophages we show that the elimination of macrophages improves PARPi therapy and long-term tumor clearance. The addition of anti-PD-1, a therapy that stops tumor cells from inhibiting the immune system, further improved our combination therapy. Triple therapy of PARPi+ARRY-382 + anti-PD-1 increased the targeting of cancer cells by immune cells compared to the dual treatment. Our work shows that targeting macrophages enhances PARPi therapy, which can be further improved by adding anti-PD-1. Therefore, targeting macrophages during PARPi therapy could improve patient outcomes.
