Nature | Application of Neoadjuvant Immunotherapy in Mismatch Repair-Profitient Colon Cancer

This study reveals the potential efficacy of neoadjuvant immunotherapy in mismatch repair-proficient (pMMR) colon cancer and identifies several possible biomarkers, such as TP53 mutations, Ki-67 expression, and chromosomal genomic instability, providing a theoretical basis for precision treatment in patients with this disease.

Literature Overview
This article, 'Application of Neoadjuvant Immunotherapy in Mismatch Repair-Profitient Colon Cancer', published in the journal Nature, reviews and summarizes the clinical efficacy and biomarker research of neoadjuvant immunotherapy in mismatch repair-proficient colon cancer, highlighting its application prospects in early-stage disease. Through clinical and molecular analyses, the article reveals potential mechanisms by which some patients respond to immunotherapy, providing directions for future research.

Background Knowledge
Mismatch repair-proficient (pMMR) colon cancer accounts for 85% of non-metastatic colon cancer cases and typically shows poor response to immune checkpoint blockade (ICB) therapy. However, neoadjuvant therapy has shown some efficacy in locally advanced disease, particularly in the DNA mismatch repair-deficient (dMMR) subtype, which may be related to higher tumor mutation burden (TMB) and stronger immune infiltration. Nevertheless, the low mutation burden in pMMR tumors results in a lower response rate to ICB, necessitating the exploration of new treatment strategies. Studies suggest that the COX-2 pathway may influence treatment efficacy by suppressing antitumor immune responses, and combining ICB with COX-2 inhibitors (such as celecoxib) may enhance the therapeutic effect of ICB. Based on data from the phase II NICHE trial, this study explores the application and biomarkers of neoadjuvant ICB in pMMR colon cancer, providing theoretical support for future precision immunotherapy.

Research Methods and Experiments
The study enrolled 33 patients with early-stage pMMR colon cancer, of whom 17 received neoadjuvant nivolumab combined with ipilimumab, and 16 received the same regimen combined with celecoxib. The treatment duration was four weeks, followed by surgical intervention. The primary endpoints were the pathological response rate and circulating tumor DNA (ctDNA) clearance. Whole-exome sequencing, gene expression profiling, and imaging mass cytometry (IMC) were used to explore the immune microenvironment and genomic features.

Key Conclusions and Perspectives

• Among 31 patients, 26% (8 cases) showed a pathological response to neoadjuvant immunotherapy, including 6 cases with major pathological response (MPR) and 3 with pathological complete response (pCR).
• ctDNA was positive in 26 patients, and 5 out of 6 responders achieved preoperative ctDNA clearance, while 19 out of 20 non-responders remained positive, indicating that preoperative ctDNA clearance can serve as a predictive marker for treatment efficacy.
• The genomic instability score was significantly higher in responders compared to non-responders, and TP53 mutations were more common in responders (88% vs 57%).
• Patients with TP53 mutations and KRASG12 wild-type showed a higher response rate (46%), suggesting this genotype may serve as a potential biomarker.
• The proportion of Ki-67+CD8+ T cells was significantly increased in responders, indicating that T cell proliferation is associated with treatment response.
• Although celecoxib theoretically enhances ICB efficacy, no significant difference in response rates was observed between the combination and single ICB groups, suggesting no significant synergistic effect in this regimen.

Conclusion
This study systematically evaluated the efficacy of neoadjuvant immunotherapy in pMMR colon cancer for the first time, finding that some patients achieved significant pathological responses, with ctDNA clearance highly correlated with treatment response. TP53 mutations, Ki-67 expression, and genomic instability may serve as potential biomarkers to help identify patients who are likely to respond to ICB. Although celecoxib did not significantly enhance the therapeutic effect, the study revealed molecular mechanisms underlying ICB response in pMMR tumors, laying the foundation for future precision immunotherapy strategies.

Folding Stability

View Tool Details

Prediction of absolute protein stability ΔG by protein sequence inverse folding model ESM-IF. Traditional physical methods (e.g., FoldX, Rosetta, etc.) for predicting protein stability ΔG rely on high-confidence structural pdb, and if there are too many mutations, the structural confidence decreases and the prediction results are poor. Benchmark results at ProteinGym show that the generative model ESM-IF predicts protein mutation stability ΔΔG of DMS data at best-in-class level in zero-shot. The method is an extension of mutation prediction by using the ESM-IF model to directly predict the absolute ΔG value of intact protein folding stability. It was tested with a prediction error RMSE ≈ 1.5 kcal/mol and a correlation coefficient of 0.7, representing a major breakthrough in predicting the folding stability ΔΔG of proteins.