EGFR is a master switch between immunosuppressive and immunoactive tumor microenvironment in inflammatory breast cancer.
Xiaoping WangTakashi SembaGaniraju C ManyamJing WangShan ShaoFrançois BertucciPascal FinettiSavitri KrishnamurthyLan Thi Hanh PhiTroy PearsonSteven J Van LaereJared K BurksEvan N CohenJames M ReubenFei YangHu MinNicholas NavinVan Ngu TrinhToshiaki IwaseHarsh BatraYichao ShenXiang H F ZhangDebasish TripathyNaoto Tada UenoPublished in: Science advances (2022)
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.
Keyphrases
- small cell lung cancer
- epidermal growth factor receptor
- clinical trial
- tyrosine kinase
- neoadjuvant chemotherapy
- regulatory t cells
- transcription factor
- oxidative stress
- mouse model
- lymph node
- poor prognosis
- locally advanced
- randomized controlled trial
- dendritic cells
- radiation therapy
- sentinel lymph node
- binding protein
- study protocol
- cell fate