Revealing novel immunomodulatory functions of CTLA4 for improving colorectal cancer immunotherapy
Anti-PD(L)1 immune-checkpoint blockers (ICBs) created a paradigm shift for solid tumour-treatment. But, specific patient/tumour-subtypes pose stiff resistance to anti-PD(L)1 ICBs – a disparity embodied by colorectal cancer (CRC). CRC has two subtypes with opposing ICB-responses: microsatellite instable (MSI; highly responsive to anti-PD1 ICBs) vs. microsatellite stable (MSS; resistant to anti-PD1 ICBs). Surprisingly, recent clinical observations showed that anti-CTLA4/anti-PD1 ICB-regimen induces positive responses in MSS-CRC, linked to increased tumoral T cell/myeloid infiltrates. But these responses weren’t distinguished by CTLA4-relevant T cell biomarkers. This raised a provocative question: could CTLA4 have hitherto unknown immunomodulatory functions, accounting for above ‘unexplained’ success? In this project, we will use state-of-the-art and innovative immune techniques, and novel CRC mice models combined with (pre)clinical scRNAseq/immunogenomic profiling to comprehensively delineate novel immuno-modulatory functions of CTLA4 that create immune-resistance in CRC. Our project may lead to highly novel concepts whilst conceptualizing new chemo-immunotherapy and biomarker modalities for anti-CRC CTLA4-targeting.