O12.02 ERBB2 signaling drives immune cell evasion and resistance against immunotherapy in small cell lung cancer

Background Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and is characterized by its highly aggressive phenotype and its dismal outcome. Although the addition of immune checkpoint blockade to carboplatin and etoposide treatment has improved outcome in SCLC patients, SCLC cells finally acquire the ability to evade immunosurveillance and develop resistance against immune checkpoint blockade.Methods To investigate molecular mechanisms underlying immune evasion and metastasis in SCLC, we performed an integrated analysis of human and murine SCLC specimens and combined high-dimensional profiling with functional validation. Initial analysis of single-cell RNA sequencing (scRNA-seq) data revealed differentially expressed genes between primary and metastatic lesions. Loss of MHC-I in SCLC metastasis was validated in matched human and murine samples of primary and metastatic SCLC with flow cytometry and immunohistochemistry. We utilized mass spectrometry and phospho-tyrosine kinase arrays to identify signaling pathways involved in immune regulation. Functional validation of ERBB2 as relevant regulator was performed using genetic and pharmacological approaches in vitro and in autochthonous murine SCLC models. The therapeutic efficacy of combined ERBB2 inhibition and immunotherapy was assessed in autochthonous SCLC mouse models through survival analysis, single-cell and TCR sequencing and flow cytometry.Results Analysis of scRNA-seq and matched human samples revealed that metastatic SCLC exhibits a loss of MHC-I expression, suggesting a role in metastasis formation and immune evasion. Genetic knockout of MHC-I in SCLC cells markedly reduced immune cell infiltration and promoted metastasis formation in immunocompetent mouse models. We identified ERBB2 as a negative regulator of MHC-I expression and a promoter of immune-modulatory transcripts. Genetic or pharmacologic inhibition of ERBB2 restored MHC-I expression and immunogenic signaling pathways. In autochthonous SCLC mouse model ERBB2 inhibition could significantly reduce metastasis formation. Notably, the combination of ERBB2 blockade with PD-1 inhibition produced synergistic anti-tumor responses, overcoming MHC-I loss and enhancing immune infiltration resulting in deep remissions and substantial extension of survival.Conclusion Our study identifies ERBB2 signaling as a critical driver of immune evasion and metastasis in SCLC through downregulation of MHC-I. Targeting ERBB2 restores MHC-I expression, enhances immune infiltration, and synergizes with PD-1 blockade to elicit robust anti-tumor responses. These findings reveal a therapeutically actionable pathway for overcoming immunotherapy resistance in SCLC and provide a strong rationale for combining ERBB2 inhibition with immune checkpoint therapy in this aggressive malignancy.