1794P - Deciphering ERBB2-driven mechanisms that regulate tumor immune evasion and metastasis in SCLC

Background

Small-cell lung cancer (SCLC) accounts for about 15% of newly diagnosed lung cancer cases and is known for its highly aggressive nature with systemic metastasis. Thus, it is often diagnosed at an advanced stage with liver or brain metastasis, presenting a significant challenge in treatment and prognosis. Current therapy options for SCLC include chemotherapy, radiation, and immunotherapy, with ongoing investigations for targeted therapies. The role of immune checkpoint inhibitors, such as programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) blocking antibodies has been evaluated in treatment of patients with extensive-stage disease (ED) SCLC showing promise in prolonging overall survival, when combined with platinum and etoposide.

Methods

We analyzed the molecular profile of murine and human samples of primary and metastatic SCLC using IHC, phospho-kinase arrays and single-cell RNA Seq. We functionally validated ERBB2- and MHC-I-mediated effects by CRISPR-Cas9 knock-outs in co-culture experiments and in vivo. Finally, we combined ERBB2- and PD-1 blockade in an autochthonous SCLC mouse model to investigate the therapeutic potential.

Results

Analysis of matched murine and human samples of primary and metastatic SCLC revealed loss of MHC-I in SCLC metastases. Silencing MHC-I, drastically decreased immune cell infiltration and facilitated the formation of metastasis in mice with SCLC by circumventing immune surveillance. ERBB2 signaling was found to be activated in SCLC metastases, suppressing MHC-I in SCLC cells and stimulating immune modulating transcripts. Blockade of ERBB2 increased T cell dependent tumor cell killing in co-culture experiments and abrogated the formation of liver metastasis in immunocompetent SCLC mice via upregulation of MHC-I. Combining ERBB2 inhibition and anti-PD-1 targeted immune checkpoint inhibition in mice showed significantly increased survival and potential for developing new treatment approaches.

Conclusions

Our findings address the unmet need to decipher targetable mechanisms that regulate tumor immune evasion and metastasis in SCLC and strongly indicate that combined inhibition of ERBB2 and PD-1 represents a promising new therapy option to improve outcomes for SCLC patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Friedrich-Alexander Universität Erlangen-Nürnberg, Faculty of Medicine; University of Cologne, Faculty of Medicine.

Disclosure

All authors have declared no conflicts of interest.