The role of immunosuppression in the tumor microenvironment and association with social drivers of health in patients with breast cancer

Overall: This proposal aims to improve the intractable challenge of high mortality in some populations with breast cancer by engaging our unique community of patients, their treating physicians, and researchers. We will investigate differences in the suppressive immune cell composition of breast tumors from patients seen at USC and integrate these findings with identified social drivers of health (SDH) to improve rational design of clinical trials to stratify patients by differences in immunosuppression and identify potential biomarkers of response to immune checkpoint inhibition (ICI). We have yet to fully understand how the suppressive immune response contributes to observed differences in outcome for different patient populations. It has been established that some of the most common immune cell populations, such as T cells, within breast tumors differ by breast cancer subtypes. However, a comprehensive understanding of the different suppressive immune cell types has not been examined in this context. In addition, the relationship with SDH has not been investigated. I along with my co-investigators will integrate our research expertise in immune-oncology (tumor immunologists, pathologists, biomedical engineers and computational biologists) with Co-I’s in population sciences, to guide our investigation of how these findings of differences in suppressive immunity can be incorporated with SDH in patients with different subtypes of breast cancer. Project: Among patients with breast cancer seen at USC, we observe a higher percentage of young women (<50 years of age) diagnosed with breast cancer and often with more aggressive subtypes. Our knowledge of immune composition of tumors that may contribute to such outcomes is unknown. ICIs reset the tumor-specific immune response by releasing the brakes on T effector cells in the tumor microenvironment (TME), leading to durable responses with less overall toxicity, but patients with breast cancer are intrinsically resistant. One potential mechanism of intrinsic resistance to ICIs is the infiltration of the TME by myeloid derived suppressor cells (MDSCs). Due to their significant inhibition of the adaptive immune response, MDSCs have been suggested as a target for breast cancer treatment. One strategy to sensitize tumors to ICIs is by reprogramming MDSCs via epigenetic modulation. Our laboratory has been instrumental in demonstrating that decreasing the function of MDSCs, is a novel and important strategy to improve the response to ICIs. We have set up and implemented a protocol that allows us to collect specimens from all patients seen within our clinics and have begun to uncover differences in myeloid and T cells in circulation and within the TME. Our Phase I clinical trial (NCI-9844) shows a 2-week pre-treatment with entinostat, followed by the combination of entinostat + nivolumab + ipilimumab, in 20 patients with advanced breast cancer, have an overall response rate of 30%. We are planning a Phase II trial powered to determine the efficacy of this promising treatment. Determination of whether suppressor cell infiltration differs in our patients and any correlation with SDH, could identify patients most likely to benefit, and social drivers that could be targeted with interventions.