An immunological mechanism of resistance to CDK4/6 inhibitors in HR+ breast cancer

Abstract

CDK4/6 inhibitors are central to the clinical management of HR⁺HER2^- breast cancer. We have recently demonstrated that immunosuppressive, IL17-secreting γδ T cells recruited to the tumor microenvironment by a CCL2-dependent mechanism upon CDK4/6 inhibition can repolarize tumor-associated macrophages toward a CX3CR1⁺ phenotype associated with resistance to therapy.

Keywords: Circulating biomarker; TAMs; endocrine therapy; hypoxia; palbociclib; single-cell RNA sequencing.

Figure 1.

A new immunological mechanism of resistance to CDK4/6 inhibitors in HR⁺HER2⁻ breast cancer. At least in an immunocompetent mouse model of HR⁺HER2⁻ breast cancer, the therapeutic effects of the CDK4/6 inhibitor palbociclib appear to be limited by a mechanism involving: (1) CCL2 secretion by malignant cells; (2) CCL2-dependent recruitment of γδ T cells to the tumor microenvironment; (3) γδ T cell secretion of IL17; and (4) IL17-dependent enrichment of tumor-associated macrophages (TAMs) toward an immunosuppressive CX3CR1⁺ profile. By virtue of its ability to (at least initially) select for hypoxic, CCL2-incompetent tumor regions, hypofractionated radiation therapy (RT) may be effectively used to avert this resistance mechanism, hence representing a promising therapeutic partner for CDK4/6 inhibitors in the clinic. Whether blocking IL17 or repolarizing CX3CR1⁺ TAMs toward an immunostimulatory state with CSF1R inhibitors may also constitute clinically viable approaches to limit resistance to CDK4/6 blockers in patients with advanced/metastatic HR⁺HER2⁻ breast cancer remains to be formally elucidated.