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Abstract Background Currently, several randomized controlled trials (RCTs) have been conducted to investigate the efficacy of combining immune checkpoint inhibitors (ICIs) with chemotherapy as a first-line treatment for advanced or recurrent endometrial cancer; however, the optimal treatment strategy remains undetermined. Methods A comprehensive search of online databases was conducted to identify RCTs published until December 31, 2023. Network meta-analysis was performed to evaluate PFS, OS, TRAEs, irAEs, and the ranking of different treatment regimens. Results A total of 2702 patients from five RCTs (six reports) were included in the analysis. The combination therapy of ICIs significantly prolonged PFS (HR = 0.69, 95%CI 0.63–0.76, p

Background: Currently, several randomized controlled trials (RCTs) have been conducted to investigate the efficacy of combining immune checkpoint inhibitors (ICIs) with chemotherapy as a first-line treatment for advanced or recurrent endometrial cancer; however, the optimal treatment strategy remains undetermined. Methods: A comprehensive search of online databases was conducted to identify RCTs published until December 31, 2023. Network meta-analysis was performed to evaluate PFS, OS, TRAEs, irAEs, and the ranking of different treatment regimens. Results: A total of 2702 patients from five RCTs (six reports) were included in the analysis. The combination therapy of ICIs significantly prolonged PFS (HR = 0.69, 95%CI 0.63–0.76, p < 0.0001) and OS (HR = 0.73, 95%CI 0.63–0.85, p < 0.0001) in the overall population. Among the different ICIs combinations evaluated, Durva-Olap-CP exhibited superior efficacy for both PFS and OS outcomes. In the pMMR population, both Durva-Olap-CP and Pembro-CP significantly reduced the risk of disease progression or death compared to Avelu-CP and Atezo-CP treatments; however, no significant differences were observed among various ICI combination therapies in patients with dMMR. In the dMMR population, Dostar-CP demonstrates a 42.2% probability of achieving first rank in terms of PFS, whereas in the pMMR population, Pembro-CP exhibits a 60% likelihood of securing the top position. Importantly, the toxicity associated with ICIs combination therapy was manageable and well-tolerated. Conclusions: The combination of ICIs and chemotherapy as first-line treatment for advanced or recurrent endometrial cancer has demonstrated superior survival outcomes compared to chemotherapy alone. Durva-Olap-CP exhibited the most favorable PFS and OS benefits in the overall population. In patients with dMMR, Dostar-CP showed the greatest improvement in PFS, while Pembro-CP demonstrated the most pronounced PFS benefit in patients with pMMR. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous early phase studies demonstrated the modest but durable anticancer activity of nivolumab plus regorafenib in mismatch repair-proficient (pMMR) refractory colorectal cancer, suggesting the necessity of predictive biomarkers for better patient selection. The authors evaluated clinicopathological characteristics and the tumor microenvironment to identify potential biomarkers. Pretreatment albumin, MIP-1β, non-liver metastatic disease and regulatory T-cell infiltration may be potential predictive biomarkers of regorafenib/nivolumab in pMMR colorectal cancer. Previously, we reported the modest but durable anticancer activity of regorafenib/nivolumab in mismatch repair-proficient (pMMR) refractory colorectal cancer in our I/Ib study. Our finding suggests the necessity of biomarkers for better selection of patients. Baseline clinical and pathological characteristics, blood and tumor samples from the patients in the trial were collected and evaluated to discover potential biomarkers. The obtained samples were assessed for immunohistochemistry, ELISA and RNA sequencing. Their correlations with clinical outcome were analyzed. A high albumin level was significantly associated with improved progression-free survival (PFS), overall survival (OS) and disease control. Non-liver metastatic disease showed prolonged PFS and OS. Low regulatory T-cell (Treg) infiltration correlated with prolonged PFS. Low MIP-1β was associated with durable response and improved OS significantly. Upregulation of 23 genes, including CAPN9, NAPSA and ROS1, was observed in the durable disease control group, and upregulation of 10 genes, including MRPS18A, MAIP1 and CMTR2, was associated with a statistically significant improvement of PFS. This study suggests that pretreatment albumin, MIP-1β, non-liver metastatic disease and Treg infiltration may be potential predictive biomarkers of regorafenib/nivolumab in pMMR colorectal cancer. Further studies are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

Abstract Background Galectin-9 is a member of the galectin family and has been reported to have a tumor-promoting or antitumor effect in response to the immune microenvironment. However, the immunomodulatory effect of galectin-9 in colorectal cancer (CRC) remains unclear. The antigen presentation and antitumor immune effects of galectin-9 in CRC were examined in this study. Methods The expression of galectin-9, dendritic cell markers (CD208 and CD1a), T-cell markers (CD3 and CD8) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) was assessed using immunohistochemistry in CRC samples. The correlation between galectin-9 and immune cells or immunomodulatory factors was also evaluated via multiple gene expression databases. Results The level of galectin-9 was decreased in mismatch repair-proficient patients compared with mismatch repair-deficient patients (p = 0.0335). GSEA showed that the regulatory mechanism of galectin-9 in CRC was related to a variety of immune pathways. Galectin-9 expression was strongly correlated with immune cell infiltration and immunomodulators (all p

Summary: Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months’ follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4–15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0–not evaluable) and 1.8 months (95% CI 1.8–2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Background: Galectin-9 is a member of the galectin family and has been reported to have a tumor-promoting or antitumor effect in response to the immune microenvironment. However, the immunomodulatory effect of galectin-9 in colorectal cancer (CRC) remains unclear. The antigen presentation and antitumor immune effects of galectin-9 in CRC were examined in this study. Methods: The expression of galectin-9, dendritic cell markers (CD208 and CD1a), T-cell markers (CD3 and CD8) and mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) was assessed using immunohistochemistry in CRC samples. The correlation between galectin-9 and immune cells or immunomodulatory factors was also evaluated via multiple gene expression databases. Results: The level of galectin-9 was decreased in mismatch repair-proficient patients compared with mismatch repair-deficient patients (p = 0.0335). GSEA showed that the regulatory mechanism of galectin-9 in CRC was related to a variety of immune pathways. Galectin-9 expression was strongly correlated with immune cell infiltration and immunomodulators (all p < 0.0001). In the relationship between galectin-9 expression and the infiltration of DCs, there was a negative correlation in CD1a + immature DCs (R = -0.263, p = 0.042). A strong positive correlation was observed in CD208 + mature DCs (R = 0.391, p < 0.01). Patients with high galectin-9 expression also exhibited abundant CD8 + T-cell and CD3 + T-cell infiltration. Conclusion: Collectively, our findings provide evidence that galectin-9 may increase the antitumor immune response of patients with CRC. DCs play an important role in galectin-9-mediated antitumor immune responses, which provides further insight into the development of immunotherapy. [ABSTRACT FROM AUTHOR]

In 2022, the KEYNOTE-775 (NCT03517449) study showed that pembrolizumab plus lenvatinib (PL) has more benefits than traditional chemotherapy as a first-line regimen to treat patients with mismatch repair-proficient (pMMR) advanced endometrial cancer (aEC). However, given the high cost of immuno-targeted therapy, the widespread use among patients remains uncertain. Therefore, we conducted a cost-effectiveness comparison between PL and chemotherapy. We evaluated the cost-effectiveness of PL versus chemotherapy over 7 years by developing a comprehensive Markov model, included 697 patients, that calculated total cost, life-years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) at a willingness-to-pay (WTP) threshold of $150,000 per QALY. The robustness of the model was evaluated by one-way, two-way, and probabilistic sensitivity analyses. In addition, we also performed subgroup analyses. Chemotherapy yielded a mean survival of 0.705 QALYs (0.901 LYs) per patient and was associated with a mean cost of $163,777. PL was associated with an incremental cost of $38,582 and an additional 0.349 QALYs, leading to an ICER of $110,401 per QALY as compared to chemotherapy. The cost of pembrolizumab had a significant impact on ICER. At the assumed WTP threshold of $150,000 per QALY, approximately 79.2% of simulations show cost-effectiveness occurs in PL. Results of the subgroup analysis showed that PL was the most cost-effective regimen for patients who had previously received 1-line of therapy. For patients with pMMR aEC, the PL strategy may be the most cost-effective strategy at a WTP of $150,000 from the economic perspective of the United States. • The Markov model was first established based on the phase III trial of KEYNOTE-775. • We evaluated the cost-effectiveness of pembrolizumab plus lenvatinib for patients with pMMR aEC. • The ICER of pembrolizumab plus lenvatinib versus chemotherapy was $110,401/QALY. • The pembrolizumab plus lenvatinib may be the most cost-effective strategy for pMMR aEC in the US. [ABSTRACT FROM AUTHOR]

Background: Cohorts A, C, and E of the phase Ib KEYNOTE-651 study evaluated pembrolizumab + binimetinib ± chemotherapy in microsatellite stable/mismatch repair-proficient metastatic colorectal cancer., Patients and Methods: Patients received pembrolizumab 200 mg every 3 weeks plus binimetinib 30 mg twice daily alone (cohort A; previously treated with any chemotherapy) or with 5-fluorouracil, leucovorin, oxaliplatin (cohort C; previously untreated) or 5-fluorouracil, leucovorin, irinotecan (cohort E; previously treated with 1 line of therapy including fluoropyrimidine + oxaliplatin-based regimen) every 2 weeks. Binimetinib dose-escalation to 45 mg twice daily was planned in all cohorts using a modified toxicity probability interval design (target dose-limiting toxicity [DLT], 30%). The primary endpoint was safety; investigator-assessed objective response rate was secondary., Results: In cohort A, 1/6 patients (17%) had DLTs with binimetinib 30 mg; none occurred in 14 patients with 45 mg. In cohort C, 3/9 patients (33%) had DLTs with binimetinib 30 mg; dose was not escalated to 45 mg. In cohort E, 1/5 patients (20%) had DLTs with binimetinib 30 mg; 5/10 patients (50%) had DLTs with 45 mg. Enrollment was stopped in cohort E binimetinib 45 mg and deescalated to 30 mg; 2/4 additional patients (50%) had DLTs with binimetinib 30 mg (total 3/9 [33%] had DLTs with binimetinib 30 mg). Objective response rate was 0% in cohort A, 9% in cohort C, and 15% in cohort E., Conclusion: Per DLT criteria, binimetinib + pembrolizumab (cohort A) was tolerable, binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, oxaliplatin (cohort C) did not qualify for binimetinib dose escalation to 45 mg, and binimetinib + pembrolizumab + 5-fluorouracil, leucovorin, irinotecan (cohort E) required binimetinib dose reduction from 45 to 30 mg. No new safety findings were observed across cohorts. There was no apparent additive efficacy when binimetinib + pembrolizumab was added to chemotherapy. Data did not support continued enrollment in cohorts C and E., Competing Interests: Disclosure E. X. Chen reports advisory/consultancy roles from AstraZeneca, Eisai, and GSK; research funding to their institution from AstraZeneca, Merck & Co., Inc., Rahway, NJ, USA, BMS, Novartis, Roche, Zymeworks, and 1Globe. P. Kavan reports advisory/consultancy role with Merck; Expert Testimony for Merck & Co., Inc., Rahway, NJ, USA; and an institutional educational grant to their institution. M. Tehfe reports advisory/consultancy roles with Merck & Co., Inc., Rahway, NJ, USA, BMS, Taiho, and Pfizer; and speaker bureau for BMS and Taiho. J. S. Kortmansky reports research funding to their institution from Merck & Co., Inc., Rahway, NJ, USA and Genentech. M. B. Sawyer reports honoraria from Ipsen, BMS, Mylan, Amgen, AstraZeneca, Eisai, Sandoz, Celgene, Servier, Novartis, Leo, Taiho, and Shire; advisory/consultancy roles with AstraZeneca, Leo, and Immuneering; expert testimony for AstraZeneca; research funding to their institution from AstraZeneca and BMS; and travel/accommodation expenses from Ipsen. E. G. Chiorean reports advisory/consultancy roles with Astellas, Bayer, Cardiff, Foundation, G1 Therapeutics, Ipsen, Noxxon, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, and Stemline; research funding to their institution from Aadi, Biosplice, BioMed Valley, Boehringer-Ingelheim, Clovis, Corcept, Erasca, Fibrogen, Lona, Merck & Co., Inc., Rahway, NJ, USA, Novartis, Rafael, and Stemline; and travel/accommodation from G1 Therapeutics. C. H. Lieu reports research funding to their institution from Merck & Co., Inc., Rahway, NJ, USA. M. Fakih reports advisory/consultancy roles with AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Mirati, Nouscom, PsiOxus, Roche/Genentech, and Taiho. K. Spencer reports advisory/consultancy roles from QED Therapeutics, Helsinn, Lynx Group, and Caris. C. Li, P. Leconte, and D. Adelberg report employment with Merck & Co., Inc., Rahway, NJ, USA; P. Leconte and D. Adelberg report stock ownership at Merck & Co., Inc., Rahway, NJ, USA. R. Kim reports honoraria from Taiho; advisory/consultancy roles with Bayer Servier, Ipsen and Roche; and speaker bureau for Eisai, Pfizer, and Incyte. B. Polite, L. Wong, and J. Chaves report no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Background: The phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer., Patients and Methods: Patients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory., Results: Thirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3 or 4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3 or 4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, PD-L1 combined positive score and T-cell-inflamed gene expression profiles were higher and HER2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed., Conclusion: Pembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration., Gov Identifier: ClinicalTrials.gov; NCT03374254., Competing Interests: Disclosure R. Kim reports honoraria from Taiho; advisory/consultancy roles with Bayer Servier, Ipsen, and Roche; and speakers bureau for Eisai, Pfizer, and Incyte. M. Tehfe reports advisory/consultancy roles with Merck & Co., Inc., Rahway, NJ, USA, BMS, Taiho, and Pfizer; and speakers bureau for BMS and Taiho. P. Kavan reports advisory/consultancy role with Merck; expert testimony for Merck & Co., Inc., Rahway, NJ, USA; and an institutional educational grant to their institution. J. S. Kortmansky reports research funding to their institution from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and Genentech. E. X. Chen reports advisory/consultancy roles from AstraZeneca, Eisai, and GSK and research funding to their institution from AstraZeneca, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, BMS, Novartis, Roche, Zymeworks, and 1Globe. C. H. Lieu reports advisory/consultancy roles with Natera; and research funding to their institution from Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. M. Fakih reports advisory/consultancy roles with AstraZeneca, Bayer, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Mirati, Nouscom, PsiOxus, Roche/Genentech, and Taiho. K. Spencer reports advisory/consultancy roles with QED Therapeutics, Helsinn, Lynx Group, and Caris. Q. Zhao reports stock ownership at Merck & Co., Inc., Rahway, NJ, USA. R. Predoiu, C. Li, P. Leconte, and D. Adelberg report employment with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. P. Leconte and D. Adelberg report stock ownership at Merck & Co., Inc., Rahway, NJ, USA. E. G. Chiorean reports advisory/consultancy roles with Astellas, Bayer, Cardiff, Foundation, G1 Therapeutics, Ipsen, Noxxon, Novartis, Merck & Co., Inc., Rahway, NJ, USA, Pfizer, and Stemline; research funding to their institution from Aadi, Biosplice, BioMed Valley, Boehringer Ingelheim, Clovis, Corcept, Erasca, Fibrogen, Lona, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, Novartis, Rafael, and Stemline; and travel/accommodations from G1 Therapeutics. J. Chaves and L. Wong report no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract Background Currently, mismatch repair-deficient (dMMR) status is a promising candidate for targeted immune checkpoint inhibition therapy in colorectal cancer (CRC) patients, however, the potential immunological mechanism has not yet been well clarified and some other predictors need to be excavated as well. Methods We collected 330 CRC patients by the match of mismatch repair-proficient (167) and dMMR (163), explored the relationship between MMR status and some important immune molecules including MHC class I, CD3, CD4, CD8, CD56, programmed death-1 and programmed death ligand-1, and investigated the risk factors for dMMR status as well as low MHC class I expression. The Pearson Chi square test was used for analyzing the associations between clinicopathological and immune characteristics and MMR status, and two categories logistic regression model was used for univariate and multivariate analysis to predict the odds ratio of risk factors for dMMR status and low MHC class I expression. Results Multivariate logistic regression analysis showed that low MHC class I and CD4 expression and high CD8 expression were significant risk factors for dMMR status [odds ratio (OR) = 24.66, 2.94 and 2.97, respectively; all p

The classification of tumor microenvironments according to the presence or absence of tumor infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) expression has been used to predict the efficacy of immune checkpoint inhibitor antibodies in several cancer types, not including colorectal cancer (CRC). The current study investigated the TIL/PD-L1 status of patients with CRC, particularly patients who presented as mismatch repair-proficient (pMMR) and mismatch repair-deficient (dMMR). A total of 243 patients with CRC were enrolled and defined as pMMR (121 patients) or dMMR (122 patients). Using Pearson's χ2 test and multivariable multinomial logistic regression analysis, the associations between MMR status, TIL presence and PD-L1 expression were investigated, in addition to the association between TIL/PD-L1 status and clinicopathological features. The results demonstrated that the dMMR group more frequently exhibited TIL+ (85/122 vs. 61/121) and PD-L1+ (49/122 vs. 32/121) phenotypes compared with the pMMR group. PD-L1+ expression was identified in 42.4% of TIL+ cases in the dMMR group, while only 18.0% of TIL+ cases were PD-L1+ in the pMMR group. High programmed death-1 expression and dMMR status were revealed as two independent risk factors for TIL+ PD-L1+ status. In conclusion, compared with the pMMR group, the dMMR group was more likely to present with a TIL+ PD-L1+ status, which suggests that a TIL+ PD-L1+ tumor microenvironment may partly contribute to the improved response of dMMR patients to anti-PD-1/L1 therapy. [ABSTRACT FROM AUTHOR]

Background: Mismatch repair-proficient (pMMR) colorectal cancers (CRCs) are thought to be primarily resistant to immune checkpoint inhibitor (ICI) monotherapy. However, recent clinical trials have reported that early-to-mid stage (non-metastatic) CRC responds well to ICI monotherapy. We hypothesized that the efficacy of immunotherapy is linked to a series of gene expression profiles that can characterize the pMMR CRC disease stage., Methods: Using The Cancer Genome Atlas (TCGA) CRC data sets, we first investigated transcriptomic features that continuously changed (were continuously upregulated or downregulated) with pMMR CRC disease-stage progression. We defined these gene sets as stage-associated genes. The deconvolution algorithm then enriched these genes with the dynamic changes in the cell type populations of the CRC tumor microenvironment (TME). Finally, the stage-associated genes were cross-referenced to the current transcriptome profile data on ICI treatment of pMMR CRC, which revealed the gene set specifying an effective pMMR tumor response., Results: In total, 774 genes were found to increase in expression and 845 genes to decrease in expression as the stage increased. Using deconvolution methods, we discovered 2 major disease stage-associated alterations in the cellular composition of pMMR CRCs, including changes in cell types involved in host immune responses and tumor cell metastasis. The central memory CD8 + T cell population decreased as the pMMR CRC disease stage increased, but the endothelial cell populations associated with proliferation and metastasis increased. Using a different cell type annotation set (LM22), we discovered that as the disease progressed, M1 macrophages and CD8 + T cells decreased in the TME. In mismatch repair-deficient patients with CRC, however, such a decrease was not observed. Finally, we identified 27 signature genes that can be used to assess ICI efficacy in treatment-naïve patients with pMMR CRC., Conclusions: The current study sought to identify the underlying molecular mechanisms, pathways, and cell landscapes that explain why early-to-mid stage pMMR CRC responds well to ICI treatment. This analysis might be valuable for the selection of patients who might benefit from immunotherapeutic strategies., Competing Interests: Conflicts of interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-1070/coif). The authors have not conflict of interest to declare., (2022 Journal of Gastrointestinal Oncology. All rights reserved.)