Breast cancer, the second most common cancer in the United States, can result from a number of cellular misregulations, such as deficiencies in the DNA-repairing breast cancer gene, BRCA. Typically, BRCA-associated breast cancer is treated with poly ADP ribose polymerase (PARP) inhibitors and, recently, clinical trials have investigated pairing PARP inhibitor therapy with immunotherapy. Based on preclinical data from Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) investigators as well as others, it was expected that this combination would recruit and activate T cells, the cells which induced tumor cell killing. While the combination trials have been well tolerated and yielded measurable activity, response rates have not been better than PARP inhibitor monotherapy. This surprise led researchers to question what in the tumor microenvironment is skewing these rates. A team of DF/BWCC researchers confronted this question, finding macrophage-mediated immune suppression is the weak spot of PARP inhibition treatment. Findings are published in Nature Cancer.
"The question that drove our research was: Why has the PARP inhibitor plus immunotherapy not been a home run?" said Jennifer Guerriero, PhD, senior author and member of the Brigham's Division of Breast Surgery and director of the Dana-Farber Breast Tumor Immunology Laboratory. "Our findings suggest that there's something else in the tumor microenvironment limiting the ability for T cells to be activated, and that something else is likely macrophages, which we found become highly suppressive after PARP inhibitor therapy."
Similar to BRCA proteins, PARP proteins act to repair damaged DNA; in tumors, inhibiting DNA repairs means cancer cell death, so the combined elimination of BRCA and PARP repair mechanisms induce cancer cell death. PARP inhibitors recruit T cells, which are required for the body to recognize the presence of cancerous cells.
Like T cells, macrophages are another type of immune cell, which is recruited to wounds to patch them up. With cancer, macrophages are recruited to tumor sites to repair, strengthen and, consequentially, exacerbate the tumor state. The team found an abundance of macrophages expressing a receptor necessary for their survival, CSF-1R, present in cancerous tissue after PARP inhibition treatment. Therefore, they hypothesized that targeting CSF-1R-positive macrophages (a particularly suppressive macrophage type) in combination with PARP inhibition would lead to an enhanced anti-tumor response.
Since CSF1R-positive macrophages exacerbate the tumor state, disabling these macrophages seemed an important therapeutic target for investigators. Using a triple-negative breast cancer BRCA-deficient mouse model, the team characterized these suppressive macrophages by assessing T cell and macrophage responses to different therapies and combinations of therapies.
When PARP and CSF1R inhibition therapies were combined, there were dramatic anti-tumor responses seen in the survival graph, with the combination extending the median overall mouse survival rate by 100 days. Furthermore, the triple combination of PARP inhibitor, CSF-1R inhibitor, and SREBP1 (a key regulator of lipid metabolism) inhibition was able to completely eliminate tumors in the aggressive triple-negative breast cancer mouse model. Researchers inferred from this therapeutic success that the PARP inhibitor directly affects how suppressive the macrophages are in the tumor microenvironment.
While breast cancer tissue is often well characterized before treatment, biopsies of tissue after treatment begins could provide more nuance to the characterization of these actors. Importantly, elucidating the mechanisms for PARP and macrophages will be critical in developing effective therapies and moving forward with clinical translation.
"At Dana-Farber/Brigham and Women's Cancer Center we have the opportunity to work closely with our clinical colleagues and ask these really important questions that will be critical to identify better biomarkers so we can know if patients should be switched to better therapies," said Guerriero. "I want to be very optimistic about the use of PARP inhibitors - they are a game changer for patients with BRCA-deficient cancers, and their application is not just limited to breast cancers. While we might have expected better responses with the combination of PARP inhibitors with immunotherapy, there's now the opportunity to think about what else is in the tumor that may be limiting the efficacy of the combination."
Funding for this research was provided by the Dana-Farber Cancer Institute/Eli Lilly & Co. Research Collaboration, the Dana-Farber/Harvard Cancer Center (DF/HCC) Specialized Program of Research Excellence (SPORE) in Breast Cancer P50 CA1685404 Career Enhancement Award, the Susan G. Komen Foundation Career Catalyst Award CCR18547597, the Terri Brodeur Breast Cancer Foundation, the Breast Cancer Research Foundation, the Ludwig Center at Harvard, the Center for Cancer Systems Pharmacology NCI U54-CA225088, Eli Lilly, NIH/NHLBI (K08 HL128802 R01 CA090687 and P50 CA1685404), the Rob and Karen Hale Distinguished Chair in Surgical Oncology, the Spanish Ministerio de Economia, Industria y Competitividad (grant SAF2017-83565-R) and the Fundación Cientifica de la Asociacion Española Contra el Cancer (AECC) (grant PROYEI6018YELA).
Paper Cited: Mehta, A, et al. "Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer" Nature Cancer DOI: 10.1038/s43018-020-00148-7
