Distinct profiles of proliferating CD8+/TCF1+ T cells and CD163+/PD-L1+ macrophages predict risk of relapse differently among treatment-naïve breast cancer subtypes

Abstract

Immunophenotypic analysis of breast cancer microenvironment is gaining attraction as a clinical tool improving breast cancer patient stratification. The aim of this study is to evaluate proliferating CD8 + including CD8 + TCF1 + Τ cells along with PD-L1 expressing tissue-associated macrophages among different breast cancer subtypes. A well-characterized cohort of 791 treatment-naïve breast cancer patients was included. The analysis demonstrated a distinct expression pattern among breast cancer subtypes characterized by increased CD8 + , CD163 + and CD163 + PD-L1 + cells along with high PD-L1 status and decreased fraction of CD8 + Ki67 + T cells in triple negative (TNBC) and HER2 + compared to luminal tumors. Kaplan-Meier and Cox univariate survival analysis revealed that breast cancer patients with high CD8 + , CD8 + Ki67 + , CD8 + TCF1 + cells, PD-L1 score and CD163 + PD-L1 + cells are likely to have a prolonged relapse free survival, while patients with high CD163 + cells have a worse prognosis. A differential impact of high CD8 + , CD8 + Ki67 + , CD8 + TCF1 + T cells, CD163 + PD-L1 + macrophages and PD-L1 status on prognosis was identified among the various breast cancer subtypes since only TNBC patients experience an improved prognosis compared to patients with luminal A tumors. Conversely, high infiltration by CD163 + cells is associated with worse prognosis only in patients with luminal A but not in TNBC tumors. Multivariate Cox regression analysis in TNBC patients revealed that increased CD8 + [hazard ratio (HR) = 0.542; 95% confidence interval (CI) 0.309-0.950; p = 0.032), CD8 + TCF1 + (HR = 0.280; 95% CI 0.101-0.779; p = 0.015), CD163 + PD-L1 + (HR: 0.312; 95% CI 0.112-0.870; p = 0.026) cells along with PD-L1 status employing two different scoring methods (HR: 0.362; 95% CI 0.162-0.812; p = 0.014 and HR: 0.395; 95% CI 0.176-0.884; p = 0.024) were independently linked with a lower relapse rate. Multivariate analysis in Luminal type A patients revealed that increased CD163 + was independently associated with a higher relapse rate (HR = 2.360; 95% CI 1.077-5.170; p = 0.032). This study demonstrates that the evaluation of the functional status of CD8 + T cells in combination with the analysis of immunosuppressive elements could provide clinically relevant information in different breast cancer subtypes.

Keywords: Luminal breast cancer; Prognosis; T cell state; Triple-negative breast cancer; Tumor-associated macrophages; Tumor-infiltrating lymphocytes.