Toll Like Receptor 4 and IFNγ Signalling axis as a therapeutic target in Triple negative Breast Cancer

Triple Negative Breast Cancer (TNBC) is a hormone-receptor-negative (ER/PR/Her2)- subtype of breast cancer which has an immunogenic character and shows extensive molecular heterogeneity. TLRs (Toll like receptors) are a class of pattern recognition receptors regulating innate immune response. In the present study, we want to envisage the immunomodulatory role of TLR4 in TNBC. The TLR expression was assessed in TNBC tumors using qPCR/flowcytometry/multiplex immunofluorescence imaging. Also, the same was compared using TNBC-TCGA datasets. Also, the correlation of TLR expression with distinct cytokines was compared in TNBC tumors using ELISA and by analysis of TNBC-TCGA transcriptome datasets. A variable pattern of TLR expression (TLR 3/4/6/9) was observed in TNBC tumors with comparably higher expression in TIL (Tumor-infiltrating lymphocyte)-enriched TNBC tumors than TIL-low tumors. Interestingly, TLR4 expression was observed to be higher in tumor cells (CDH1+) compared to that in stromal cells (CDH1-) within TNBC tumors. The TLR4 expression was found to significantly correlate with IL10/IFNϒ cytokine expression in TNBC tumors. Analysis of TNBC-TCGA datasets predicted longer survival probability in TIL-enriched TNBC patients with high TLR 4 and IFNϒ expression. This study suggests that targeting the TLR4 and IFNϒ signaling could be a potential therapeutic target in TNBC.