Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with poor survival rates. Immune checkpoint inhibitors (ICIs) are typically most effective in cancers with high mutation burdens. However, ICIs have been less effective in SCLC compared to other highly mutated malignancies. Distinct subtypes of SCLC have been defined according to expression of specific neuroendocrine transcription factors ASCL1 (SCLC-A), NEUROD1 (SCLC-N), and POU2F3 (SCLC-P). An additional “inflamed” subtype, termed SCLC-I, lacks expression of these transcription factors but shows high expression of antigen presentation pathway (APP) genes including MHC-I1. Importantly, SCLC-I tumours have shown improved responses to ICI therapy. SCLC cells can transition between neuroendocrine and inflamed (SCLC-I) states. This transition likely occurs through epigenetic plasticity, though the underlying mechanisms remain largely unknown.
Our lab is investigating mechanisms of epigenetic switching in SCLC to uncover strategies for improving ICI efficacy. Previously we identified a role for the Polycomb Repressive Complex 2 (PRC2) in silencing MHC-I genes in cancer cells2. Here, we performed targeted epigenetic CRISPR-Cas9 screens across a panel of SCLC cell lines to identify key regulators of subtype plasticity in SCLC. Our screens confirmed PRC2 as a key complex in maintaining the neuroendocrine, immune silent state in SCLC. Beyond PRC2, several other epigenetic complexes were also found to contribute to this immune silent phenotype. Genetic and pharmacological inhibition of these complexes in SCLC cells induced MHC-I expression and promoted a global inflammatory response. This inhibition also led to derepression of bivalent genes marked by H3K27me3 and H3K4me3, including APP genes. Combining these epigenetic targeting strategies with anti-PD-1 therapy in vivo further enhanced tumour suppression. Overall, our findings highlight the potential of targeting specific epigenetic regulators in SCLC to improve responses to ICI therapy.