Correlation of gene expression analysis of tumor-infiltrating CD4+ cells with immune function and survival according to different breast cancer (BC) molecular subtypes.

Sotiriou C, Equeter C, El Ouriaghli F, Haibe-Kains B, Durbecq V, Larsimont D, Igniatiadis M, Desmedt C, Willard-Gallo K and Piccart MJ

Background: Several studies have demonstrated the role of the adaptive immune response in controlling growth and recurrence of human tumors. However, its role in BC remains largely unknown. Here, we aim to gain further insight into the functional defects characterizing breast tumor-infiltrating T cells and to assess their relationship with BC subtypes and clinical outcome.

Methods: CD4+ T cells were purified from 10 primary invasive ductal breast carcinomas and a whole genome gene expression profiling analysis was performed using Affymetrix Human GeneChip Arrays. A tumor-infiltrating CD4+ signature, reflecting immune response, was computed, and its association with BC subtypes and clinical outcome was assessed using several external publicly available datasets, including more than 2500 untreated and systemically treated BC patients.

Results: A gene expression analysis of purified CD4+ cells revealed several differences in immune response according to the BC subtypes from which they derived. Interestingly, CD4+ signature levels were higher in ER-/PR-/HER2- (“triple-negative”) and HER2+ tumors compared to ER+/HER2- (“luminal”) tumors, suggesting several functional differences in immune response of CD4+ T cells according to BC subtypes. Higher levels of CD4+ signature were statistically associated with better survival only within the ER-/PR-/HER2- (HR=0.733; 95%CI: {0.620 to 0.867}; p<0.0001) and the HER2+ subtypes (HR=0.790; 95%CI: {0.635 to 0.982}; p=0.033), but not in the ER+ (“luminal”) subgroup. This positive association with survival was even stronger when adjuvant chemotherapy was administered. Of interest, the CD4+ signature was the only prognostic signature, compared to several others, showing a statistically significant prognostic value in the already high-risk “triple-negative” subgroup.

Conclusions: This study is the first to demonstrate differences in the immune function of tumor-infiltrating CD4+ cells according to BC molecular subtypes. Our results suggest that only the already high-risk “triple-negative” and HER2+ tumors may be suitable candidates for adjuvant immunotherapy strategies.