Viral mimicry redirects immunosuppressed colorectal tumour landscapes towards a proinflammatory and CMS1-like regenerative state.
Corry SM., Sakhnevych S., Mohamed NE., Malla SB., Byrne R., Young A., Amirkhah R., Bull C., Lees A., Redmond K., Lannagan TRM., Ridgway RA., Taggart FR., Fisher NC., Maughan T., Lawler M., Campbell AD., Leedham SJ., Ryan AE., Longley DB., Small DM., Sansom OJ., Dunne PD.
In colorectal cancer (CRC), tumours classified 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 polyinosinic:polycytidylic acid, 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 poor-prognostic tumours, by reprogramming stem cell states and activation of an innate-adaptive anti-metastatic response.