Evaluation of the immune landscape associated with the efficacy of immunotherapy in patients with triple-negative breast cancer: Starlet study, synergy between research and clinical work.

Abstract

e12568 Background: Neoadjuvant chemotherapy (NACT) is the standard treatment for early-stage TNBC and achieving a pathological complete response (pCR) is an essential prognostic factor. Recently, by applying a morphology-guided spatial transcriptomic approach, we showed that intratumoral infiltrating lymphocytes (iTILs) and stromal Natural Killer (NK) cells are major determinants of chemotherapy efficacy in TNBC. These data underline how spatiality and molecular activation of immune cells are essential to enhance the efficacy of the NACT in TNBC. The fact that immune cells are important players in this setting is corroborated by the clinical success showed by the KEYNOTE-522 study (Schmid et al, NEJM 2020). This trial paved the way for the use of immunotherapy in TNBC, obtaining a significant improvement in the patient’s overall response. The implementation of chemotherapy with immunotherapy in the TNBC neoadjuvant treatment implicates several compelling questions, including how to further increase the percentage of pCR overcoming resistance mechanisms and how to improve the personalization of treatment, evaluating which patients can benefit from a therapy de-scalation or another combined therapeutic strategy. Methods: we enrolled 43 patients with early-TNBC treated with the KEYNOTE-522 regimen. To further clarify the immune dynamics that lead to a complete response to pembrolizumab in these patients, we collected peripheral blood before and after neoadjuvant treatment to isolate peripheral blood mononucleated cells (PBMCs). We applied asingle-cell transcriptome analysis to shape any variations in circulating immune cells occurring during neoadjuvant treatment and associated with patient response. In addition, we collected residual tumor at surgery from partial responders and derived three-dimensional organoids that recapitulate the characteristics of patient tumor. Results: Immune profiling of PBMCs indicated that patients showing pCR during NACT and immunotherapy displayed a decrease of B Lymphocytes and a concomitant enhancement of Natural Killers. We successfully established TNBC patient-derived organoids from 8 TNBC patients. Conclusions: our ongoing study is defining the immune-related molecular mechanisms driving pembrolizumab and chemotherapy response in the neoadjuvant treatment of TNBC patients. Our findings can improve our understanding of which immune populations are determinant players in anti-TNBC immune response and can be proposed as novel biomarkers of pembrolizumab efficacy during the neoadjuvant treatment.