EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer

Abstract

Inflammatory breast cancer (IBC), the most aggressive breast cancer subtype, is driven by an immunosuppressive tumor microenvironment (TME). Current treatments for IBC have limited efficacy. In a clinical trial (NCT01036087), an anti-EGFR antibody combined with neoadjuvant chemotherapy produced the highest pathological complete response rate ever reported in patients with IBC having triple-negative receptor status. We determined the molecular and immunological mechanisms behind this superior clinical outcome. Using novel humanized IBC mouse models, we discovered that EGFR-targeted therapy remodels the IBC TME by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages. These changes were due to diminishing immunosuppressive chemokine expression regulated by transcription factor EGR1. We also showed that induction of an immunoactive IBC TME by an anti-EGFR antibody improved the antitumor efficacy of an anti–PD-L1 antibody. Our findings lay the foundation for clinical trials evaluating EGFR-targeted therapy combined with immune checkpoint inhibitors in patients with cancer.

Genome-wide CRISPR screens define determinants of epithelial-mesenchymal transition mediated immune evasion by pancreatic cancer cells

“…However, our data about the immunosuppressive function for MFGE8 are in line with others, where MFGE8 expression in esophageal cancer was found to correlate with decreased CD8 + T cell infiltration, and MFGE8 impaired T cell activation in the context of transplantation ( 83 ). Furthermore, a recent study demonstrated a critical role for EGFR in creating an immunosuppressive environment in breast cancer ( 84 ).…”

Copy Number Variation in Inflammatory Breast Cancer

“…An ongoing clinical trial (NCT05177796) is evaluating the enhancement of immunotherapy by targeting the EGFR pathway with panitumumab and pembrolizumab in combination with neoadjuvant chemotherapy in TN-IBC. In a humanized mouse model study, panitumumab remodeled the IBC tumor microenvironment (TME) by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages [ 38 ]. Furthermore, panitumumab reduced the gene expression of immunosuppressive cytokines, including TGFB1, TGFB2, TGFB3, CCL2, and IL1B [ 38 ].…”

“…In a humanized mouse model study, panitumumab remodeled the IBC tumor microenvironment (TME) by increasing cytotoxic T cells and reducing immunosuppressive regulatory T cells and M2 macrophages [ 38 ]. Furthermore, panitumumab reduced the gene expression of immunosuppressive cytokines, including TGFB1, TGFB2, TGFB3, CCL2, and IL1B [ 38 ]. EGFR targeted therapy has been shown to modulate the TME in lung cancer [ 39 , 40 ].…”

Role of exosomes in non-small cell lung cancer and EGFR-mutated lung cancer

“…On the other hand, M2 macrophages exhibit potent anti-inflammatory activity, countering the pro-inflammatory response of M1 by upregulating IL-10 and downregulating IL-12 with markers including CD206, CD163 and CD68 (74). Previously, it was reported that macrophage M2 polarization is generated by the tumor microenvironment, and then polarized M2 macrophages promote tumor cell proliferation, invasion, and EMT (75)(76)(77). Researchers found that hypoxia induced tumor-associated macrophage enrichment and M2 polarization via HIF.…”