Circulating and spatial immune biomarkers of response to neoadjuvant chemotherapy and nivolumab in ER + /HER2- breast cancer: analysis of the phase II GIADA trial

Adding an ICI to neoadjuvant chemotherapy (NACT) increases pCR rates in ER+/HER2- high-risk BC, but also toxicity, highlighting the need for predictive biomarkers. We explored associations between circulating immune-mediators, spatial tumor immune architecture, and pCR in the phase II GIADA trial. Forty-three premenopausal patients with stage II–IIIA ER+/HER2− Luminal B-like BC received epirubicin-cyclophosphamide x3 followed by nivolumab and endocrine treatment. Plasma levels of 47 circulating immune-mediators were evaluated at baseline (t0), after chemotherapy (t1), and before surgery (t2). Multiplex immunofluorescence was performed on tumor biopsies at t0 and t1 to assess spatial interactions between cell subpopulations. At baseline, seven immune-mediators were significantly higher in pCR-patients: IFNγ, GROα, sCD40L, EGF, VEGF-A, PDGF-AA, PDGF-AB/B. A composite 7-cytokine score was significantly associated with pCR (OR 3.04, p = 0.017). These immune-mediators were positively associated with infiltration by specific immune cell subpopulations, including tumoral/stromal PD-L1+ macrophages and PD-1+ T-cells, and intratumoral CD4+ and CD8+GranzymeB+ cells. At baseline, spatial interactions between tumor cells and multiple immune subpopulations (CD4+, CD8+, FOXP3+ T-cells and CD68+ macrophages) were associated with pCR. At t1, interactions involving CD8+GranzymeB+ T-cells were more prominent among responders. Circulating immune-mediators and tumor-immune spatial organization are associated with pCR in high-risk ER+/HER2− BC treated with chemoimmunotherapy.