Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine carcinoma with extremely poor survival outcomes. SCLC typically possesses many mutations and potential neoantigens, theoretically making it a good target for T-cell mediated immune surveillance. However, immune checkpoint blockade (ICB) is less effective in SCLC compared to other malignancies with a similarly high mutational burden.
90% of SCLC show low/absent expression of cell surface MHC-I and we have previously shown that MHC-I genes are frequently silenced in SCLC by polycomb repressive complex 2 (PRC2). Although ICB ineffective for most patients with SCLC, a small proportion of patients have shown exceptional responses, with durable tumour eradication. These exceptional responses occur in the small subgroup of patients with MHC-I high tumours, highlighting the potential to achieve immune-mediated clearance of SCLC and underscoring the importance of understanding the mechanisms contributing to MHC-I silencing and immune evasion in these tumours.
We recently identified that Menin, a component of the MLL1/2 histone methyltransferase complexes, contributes to polycomb mediated silencing of bivalent MHC-I genes. Here, we have investigated the potentital for Menin inhibition to overcome ICB resistance in SCLC. Interestingly, genetic knockout or pharmacological inhibition of Menin restores cell surface MHC-I in human and mouse SCLC cell lines and patient derived SCLC xenografts, and leads to enhanced tumour cell killing by antigen-specific T cells. Combined Menin and PRC2 inhibition dramatically enhances the derepression of bivalent genes including MHC-I in SCLC cells and leads to activation of an inflammatory gene expression signature associated with improved ICB response in patients. Targeting Menin alone or in combination with PRC2 also enhances immune mediated clearance of SCLC following ICB. Together our findings provide a rationale for using Menin inhibitors to enhance immunotherapy responses in SCLC and other malignancies exhibiting polycomb-mediated silencing of MHC-I antigen presentation.