Immunological Impacts of Targeted and Cytotoxic Therapeutics in Breast Cancer

Abstract

Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women in the United States. Patients with invasive breast cancer are often treated systemically with targeted or cytotoxic therapies, which inhibit the growth of or kill tumor cells; however, these therapeutics can also impact non-tumor cell populations, including immune cells. The implications of these systemic effects on therapeutic response remain an open question. Together with my colleagues, I found that the CDK4/6 inhibitor, abemaciclib, promotes an anti-tumor immune response through two mechanisms: increased tumor immunogenicity and preferential inhibition of regulatory T cell proliferation. As a result, cytotoxic T cell mediated clearance of tumor cells is enhanced, and we found that the response of murine mammary carcinomas to abemaciclib is dependent, in part, on CD8+ T cells. Our studies reveal that combining CDK4/6 inhibition with immunotherapy further increases the depth and duration of response. Importantly, transcriptomic analysis of serial biopsies from breast cancer patients on a clinical trial of a CDK4/6 inhibitor revealed signatures of an enhanced immune response that were very similar to those observed in our pre-clinical models. These findings suggest that the addition of CDK4/6 inhibition may enhance response to immunotherapy. Further, my other studies using a murine model of triple negative breast cancer uncovered striking effects of systemic factors and cytotoxic therapies on lung and liver metastasis. In one version of this model, the presence of a primary mammary tumor completely abrogates experimental lung metastasis, via mechanisms independent of the adaptive immune response. Additionally, direct effects of cytotoxic chemotherapy on the host systemic environment have no impact on lung metastasis, but paradoxically, enhance liver metastasis, an effect that may be mediated by liver-specific changes induced by chemotherapy. These findings have the potential to spur studies that may increase our ability to predict the likelihood of a patient developing overt distant metastases based on characteristics of their primary tumor. Additionally, my results suggest that the impact of cytotoxic chemotherapy on the liver may have unintentional, metastasis-promoting effects that could potentially be blocked in order to improve therapeutic response.