Background Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths in the US.1 Standard treatment for non-metastatic disease involves surgery plus adjuvant hormonotherapy. However, approximately 50% of patients ultimately relapse and require additional lines of treatment including chemotherapy, which is unfortunately associated with limited clinical benefits and severe toxicity. In HR+ BC patients, the efficacy of immunotherapy has also been disappointing so far. Indeed, objective responses to PD-1 blockade with pembrolizumab in women with HR+ BC have been in the range of 5–10%, with no clear advantage on survival. Thus, resistance to PD-1 blockers constitutes a major obstacle towards the implementation of immunotherapy in HR+ BC patients.
Methods To obtain insights into the immunological alterations accompanying disease relapse in HR+ BC exposed to PD-1 blockade, we harnessed a unique endogenous model of BC driven in immunocompetent mice by progesterone and a carcinogen. This model recapitulates key aspects of human luminal B BC, including a relatively ´cold´ microenvironment, hence limited sensitivity to PD-1 blockage.2 To overcome PD-1 resistance we treated mice with Flt3-L to stimulate the maturation of cross-presenting dendritic cells, and radiation therapy that can act as an adjuvant to inflame tumor micro-environment.3 In parallel, we tried to achieve complete control of the primary tumor by identifying ablative doses of fractionated radiation therapy (RT).
Results Immunotherapy (PD-1 + Flt3L), despite slowing down the tumor growth, failed to improve the overall survival (OS) of mice elicited by RT alone in a unique mouse model of HR+ BC, potentially linked to an accrued systemic immunosuppression (T cells exhaustion, and increase of Tregs). The addition of CTLA-4, even though providing an initial response, failed to improve the tumor growth and OS, due to immunoresistance (immature macrophages, and decrease in T cells and NK cells at the systemic level). Partially ablative RT doses were able to improve the OS and will be combined with PD-1 + Flt3L in the near future.
Conclusions Breaking through resistance of HR+ tumors to PD-1 blockers can direct strategies to overcome resistance in HR+ BC patients, the majority of BC patients. If successful, this can inform therapeutic approaches to enable superior therapeutic responses in patients with HR+ BC, hence significantly reducing BC-related deaths.
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