Viral mimicry redirects immunosuppressed colorectal tumour landscapes towards a proinflammatory and CMS1-like regenerative state
Corry, S. M.; Sakhnevych, S.; Mohamed, N. E.; Malla, S. B.; Byrne, R.; Young, A.; Amirkhah, R.; Bull, C.; Lees, A.; Redmond, K.; Lannagan, T.; Ridgway, R. A.; Taggart, F.; Fisher, N.; Maughan, T.; Lawler, M.; Campbell, A.; Leedham, S.; Ryan, A.; Longley, D.; Small, D.; Sansom, O.; Dunne, P. D.
Show abstract
In colorectal cancer (CRC), tumours classifier as consensus molecular subtype 4 (CMS4) have the worst prognosis and derive negligible benefit from chemotherapy. We previously described how repressed interferon-related signalling is associated with increased relapse in CMS4 tumours. Although the viral mimetic poly(I:C) can reduce liver metastasis in vivo, the initial phenotypic changes that underpin its anti-metastatic response remain poorly described, particularly in the immunosuppressed CMS4 tumour microenvironment. Here we characterise lineage-specific anti-metastatic responses induced by poly(I:C), including acute macrophage polarisation and a novel CMS1-like regenerative stem cell state, which drive pro-inflammatory microenvironmental changes in CRC. These insights enabled the development of tractable biomarkers that identify an "immune-warm" patient subset most likely to respond to poly(I:C), enriched for mismatch-repair proficient (pMMR), anti-inflammatory macrophages and CMS4-like features. The viral mimetic poly(I:C) offers a tailored treatment option for CMS4 tumours, by reprogramming stem cell states and activation of an innate-adaptive anti-metastatic response.
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