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.