Discordant prognosis of mismatch repair deficiency in colorectal and endometrial cancer reflects variation in antitumour immune response and immune escape

Abstract

Defective DNA mismatch repair (dMMR) causes elevated tumour mutational burden (TMB) and microsatellite instability (MSI) in multiple cancer types. dMMR/MSI colorectal cancers (CRCs) have enhanced T‐cell infiltrate and favourable outcome; however, this association has not been reliably detected in other tumour types, including endometrial cancer (EC). We sought to confirm this and explore the underpinning mechanisms. We first meta‐analysed CRC and EC trials that have examined the prognostic value of dMMR/MSI and confirmed that dMMR/MSI predicts better prognosis in CRC, but not EC, with statistically significant variation between cancers (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.54–0.73 versus HR = 1.15, 95% CI = 0.72–1.58; PINT = 0.02). Next, we studied intratumoural immune infiltrate in CRCs and ECs of defined MMR status and found that while dMMR was associated with increased density of tumour‐infiltrating CD3+ and CD8+ T‐cells in both cancer types, the increases were substantially greater in CRC and significant only in this group (PINT = 4.3e‐04 and 7.3e‐03, respectively). Analysis of CRC and EC from the independent Cancer Genome Atlas (TCGA) series revealed similar variation and significant interactions in proportions of tumour‐infiltrating lymphocytes, CD8+, CD4+, NK cells and immune checkpoint expression, confirming a more vigorous immune response to dMMR/MSI in CRC than EC. Agnostic analysis identified the IFNγ pathway activity as strongly upregulated by dMMR/MSI in CRC, but downregulated in EC by frequent JAK1 mutations, the impact of which on IFNγ response was confirmed by functional analyses. Collectively, our results confirm the discordant prognosis of dMMR/MSI in CRC and EC and suggest that this relates to differences in intratumoural immune infiltrate and tumour genome. Our study underscores the need for tissue‐specific analysis of cancer biomarkers and may help inform immunotherapy use. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The association between the tumor immune microenvironments and clinical outcome in low‐grade, early‐stage endometrial cancer patients

“…We found an enrichment of MMRP deficiency in samples from TIL‐rich and immune‐exclusion phenotypes. The fact that an immune‐exclusion phenotype is enriched in MMRP‐deficient tumors is supported by previous studies analyzing the singular immune microenvironment of MMRP‐deficient endometrial cancer compared with MMRP‐deficient tumors from other locations [ 45 ]. In addition, the correlation between the immune phenotypes and POLE or CTNNB1 mutation status was non‐significant.…”

METTL3 facilitates immunosurveillance by inhibiting YTHDF2-mediated NLRC5 mRNA degradation in endometrial cancer

“…The initiation and progression of EC are complicated processes, and epidemiological risk factors and genetic risk factors are well known to be responsible for the development of EC [ 1 ]. In recent years, tumor cell escape from immunosurveillance has been demonstrated to be a crucial mechanism underlying tumor development, including EC development [ 2 ]. However, the exact molecular mechanism underlying immune evasion in EC remains unclear.…”

A Focused Clinical Review of Lynch Syndrome

“… 109 This leads to a high number of immunogenic peptides that stimulate an anti-cancer immune response. 110 To overcome this, LS-associated cancer develops immune escape mechanisms namely they utilise the programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) axis. 111 This is a druggable mechanism; the development of checkpoint immune inhibitors has revolutionised the treatment of cancers with mismatch repair deficiency.…”