Interleukin-17-based cytokine signaling as a determinant for tumor immune microenvironment with prognostic value in triple-negative breast cancer

Abstract Background: Only a proportion of triple-negative breast cancer (TNBC) is immunotherapy-responsive. We hypothesized that the tumor microenvironment (TME) might influence the outcomes of TNBC and investigated the relevant signaling pathways. Methods: RNA-seq data of 115 TNBC samples and 112 normal adjacent tissues were retrieved for ESTIMATE, CIBERSORTx, X2K, KEGG, and GSVA analyses. The immune score (IS) and stromal score (SS) were calculated and correlated with the overall survival (OS) in TNBC. Finally, we validated the altered transcription factor (TF) genes in the cBioPortal. Results: The SS is a good predictor of the OS (better survival in SS-low patients; P = 0.0081). In line with these results, when compared with IS-low/SS-high patients, IS-high/SS-low patients showed a better OS (P = 0.045). Moreover, macrophages were polarized toward the M2 phenotypes in IS-low/SS-high patients (P < 0.001). Compared with IS-low/SS-high patients, CIBERSORTx also showed that IS-high/SS-low patients had an increased number of memory B cells, CD8+ T cells (14.8% vs. 3.7%, p = 0.0286), activated CD4+ memory T cells, follicular helper T cells, and activated NK cells in the TME; additionally, fewer resting NK cells were detected in the TME (P = 0.0108). Additionally, there were 284 upregulated and 367 downregulated DEGs (Differentially Expressed Genes) in IS-high/SS-low, and 187 upregulated and 183 downregulated DEGs in IS-low/SS-high patients. KEGG analysis further revealed that the DEGs were enriched in the IL-17 and cytokine-cytokine receptor interaction pathways. Of note, as per the cBioPortal platform, we discovered that 13% of ER-negative, HER2-unamplified BC patients harbored IL17RA deep deletions and 25% harbored TRAF3IP2 amplifications; interestingly, the nine altered TF genes were associated with significantly worse relapse-free survival and OS, in the context of 2,377 and 4,819 BC patients, respectively.Conclusions: The TME with different immune cell components influences the survival of TNBC patients. IS-high/SS-low patients show a better overall survival. Further studies are required to examine whether an immune/stromal state also predicts the response to immunotherapy.