In most cells, MAVS functions as the principal innate immune adaptor to transmit signals from the RIG-I and MDA5 RNA sensor genes. 20 This study also demonstrated that MAVS knockout mice display an enhanced susceptibility to CRC development, 20 which was linked to MAVS-regulated p53 stability however, the potential role of MAVS in CRC immune surveillance was not interrogated, despite its critical role in initiating innate immune responses. Given these observations, one potential mechanism for the loss of IFN signaling in CRC is reduced expression of the mitochondrial antiviral signaling gene (MAVS), which was recently reported to be reduced in CRCs, as well as lung and breast cancers. 19 Collectively, these studies suggest that the majority of CRCs may have suppressed IFN responsiveness, potentially driven by selection against innate immune genes responsible for IFN signaling. 16 17 Additional studies have also established that tumor mutations in the type I IFN pathway can confer immunotherapeutic resistance, 18 further indicating that intact type I IFN signaling in the tumor microenvironment is critical for the generation of local and systemic T cell activity required for ICI responses. 9 10 13 14 For these largely immune-non-responsive non-MSI CRCs, secondary analyses demonstrate a strongly diminished presence of infiltrating T cell and interferon (IFN) gamma signature in tumors, 15 suggesting the importance of local T cell activity for responsiveness. 9–12 However, the majority of CRCs (~85%) are mismatch repair proficient with low microsatellite instability (termed pMMR/MSI-L tumors) and have thus been largely unresponsive (~11% disease control rate) to anti-PD-1/PD-L1 ICIs. In patients with CRCs that are mismatch repair deficient with high microsatellite instability (dMMR/MSI-H tumors), high levels of neoepitopes are thought to cause enhanced T cell infiltration, allowing for anti-PD-1/PD-L1 ICI efficacy in a significant proportion of these patients (~30%–50% response rates). 4–8 This dichotomy in ICI responsiveness is well illustrated in colorectal carcinomas (CRCs). ![]() The lack of immunity against these cancers is increasingly recognized as product of tumor evolution, which selects for highly immunosuppressed tumors deficient in critical elements of innate immunity. Immune checkpoint inhibitor (ICI) antibodies targeting PD-1 and PD-L1 have revolutionized the treatment of cancer, triggering long-term regressions in a significant subset of patients with specific types of cancer 1–3 however, the majority of malignancies remain refractory to ICIs, due to a lack of pre-existing immunity and engagement of alternative immunosuppressive pathways.
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