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Involvement of the NLRC5 / MHC class I axis in human colorectal cancer immune surveillance
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Edité par CCSD -
International audience. Most of patients with colorectal cancer (CRC) without microsatellite instability fail torespond to immune checkpoint blockade (ICB) through poorly understood changes in thetumor microenvironment. Recently, we provided evidence that the tonus of tumor infiltratingT lymphocytes (TILs) is associated to the intra-tumoral activity of Caspase-1 (doi:10.3390/cancers13020189). Bulk RNA-seq analysis of CRC revealed a greater expression level of NLRfamily CARD domain containing 5 (NLRC5) in tumors with a detectable Caspase-1 activity.Given that NLRC5 is a regulator of major histocompatibility complex class I (MHC-I) antigenpresentation, we postulated that NLRC5 may modulate cancer immune surveillance andresponsiveness to ICB. We thereby evaluated the significance of the intratumoral changesin NLRC5 expression in several cohorts of patients. We show that NLRC5 is a favorableprognostic factor of overall survival in 100 CRC and of responsiveness to ICB in 45 metastaticCRC. In agreement, NLRC5 expression in KRAS wild type CRC is of better prognosis andpositively correlates with PD1/PD-L1 axis. Conversely, a negative correlation is observedbetween PRMT5, an epigenetic modifier that represses NLRC5 expression, and PD-1/PD-L1axis. Finally, functional studies using co-cultures of TILs isolated from CRC fragments andcolonic cancer cell lines show that enforced expression of NLRC5 in tumor cells enhancesthe cytotoxic activity of CD8+ TILs (cytokine production, degranulation), via a MHC-I-dependent mechanism. Overall, our findings suggest that NLRC5 could be a valuablebiomarker in CRC and that increasing the NLRC5/MHC-I axis in tumor cells could enhanceanti-tumor immunity and immunotherapeutic responses.
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