Galectin-7 Induction by EHMT2 Inhibition Enhances Immunity in Microsatellite Stability Colorectal Cancer.

BACKGROUND & AIMS: Although immunotherapy shows substantial advancement in colorectal cancer (CRC) with microsatellite instability high, it has limited efficacy for CRC with microsatellite stability (MSS). Identifying combinations that reverse immune suppression and prime MSS tumors for current immunotherapy approaches remains an urgent need. METHODS: An in vitro CRISPR screen was performed using coculture models of primary tumor cells and autologous immune cells from MSS CRC patients to identify epigenetic targets that could enhance immunotherapy efficacy in MSS tumors. RESULTS: We revealed EHMT2, a histone methyltransferase, as a potential target for MSS CRC. EHMT2 inhibition transformed the immunosuppressive microenvironment of MSS tumors into an immunomodulatory one by altering cytokine expression, leading to T-cell-mediated cytotoxicity activation and improved responsiveness to anti-PD1 treatment. We observed galectin-7 up-regulation upon EHMT2 inhibition, which converted a "cold" MSS tumor environment into a T-cell-inflamed one. Mechanistically, CHD4 repressed galectin-7 expression by recruiting EHMT2 to form a cotranscriptional silencing complex. Galectin-7 administration enhanced anti-PD1 efficacy in MSS CRC, serving as a potent adjunct cytokine therapy. CONCLUSIONS: Our findings suggest that targeting the EHMT2/galectin-7 axis could provide a novel combination strategy for immunotherapy in MSS CRC.

SET facilitates immune escape of microsatellite stability colorectal cancer by inhibiting c-Myc degradation.

Microsatellite stability (MSS) colorectal cancer (CRC) exhibits a low mutation load and poor immunogenicity, contributing to immune escape of tumor cells and less benefit from immune checkpoint blockade (ICB) treatment. The mechanisms underlying immunotherapeutic resistance in MSS CRC remain to be elucidated. Here, we identified that nuclear proto-oncogene SET is significantly higher expressed in MSS CRC compared to microsatellite instability (MSI) CRC and facilitates immune escape of MSS CRC. Mechanistically, SET represses the expression of C-C motif chemokine ligand 5 (CCL5) and upregulates mismatch repair (MMR) proteins expression in a c-Myc-dependent manner, which inhibits infiltration and migration of CD8+ T cells to tumor tissues and results in low immunogenicity in MSS CRC. In addition, we found that SET impairs ubiquitination and proteasomal degradation of c-Myc by disrupting the interaction between E3 ligase FBXW7 and c-Myc. Moreover, SET inhibition enhances the response to immunotherapy in MSS CRC in vivo. Overall, this study reveals the critical roles and posttranslational regulatory mechanism of SET in immune escape and highlights the SET/c-Myc axis as a potential target for immunotherapy of MSS CRC that have implications for targeting a unique aspect of this disease.

Node-sparing modified short-course Radiotherapy Combined with CAPOX and Tislelizumab for locally Advanced MSS of Middle and low rectal Cancer (mRCAT): an open-label, single-arm, prospective, multicentre clinical trial.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is a standard treatment for locally advanced rectal cancer. Mismatch repair-deficient locally advanced rectal cancer (LARC) was highly sensitive to PD-1 blockade. However, most rectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) subtypes for which PD-1 blockade is ineffective. Radiation can trigger the activation of CD8 + T cells, further enhancing the responses of MSS/pMMR rectal cancer to PD-1 blockade. Radioimmunotherapy offers a promising therapeutic modality for rectal cancer. Progenitor T exhausted cells are abundant in tumour-draining lymph nodes and play an important role in immunotherapy. Conventional irradiation fields include the mesorectum and regional lymph nodes, which might cause considerable damage to T lymphocytes and radiation-induced fibrosis, ultimately leading to a poor response to immunotherapy and rectal fibrosis. This study investigated whether node-sparing modified short-course irradiation combined with chemotherapy and PD-1 blockade could be effective in patients with MSS/ pMMR LARC. METHODS: This was a open-label, single-arm, multicentre, prospective phase II trial. 32 LARC patients with MSS/pMMR will receive node-sparing modified short-course radiotherapy (the irradiated planned target volume only included the primary tumour bed but not the tumour-draining lymph nodes, 25 Gy/5f, 5 Gy/f) followed by CAPOX and tislelizumab. CAPOX and tislelizumab will be started two days after the completion of radiotherapy: oxaliplatin 130 mg/m2 intravenous infusion, day 1; capecitabine 1000 mg/m2 oral administration, days 1-14; and tislelizumab 200 mg, intravenous infusion, day 1. There will be four 21-day cycles. TME will be performed at weeks 14-15. We will collect blood, tumour, and lymphoid specimens; perform flow cytometry and in situ multiplexed immunofluorescence detection; and analyse the changes in various lymphocyte subsets. The primary endpoint is the rate of pathological complete response. The organ preservation rate, tumour regression grade, local recurrence rate, disease-free survival, overall survival, adverse effects, and quality of life will also be analysed. DISCUSSION: In our research, node-sparing modified radiotherapy combined with immunotherapy probably increased the responsiveness of immunotherapy for MSS/pMMR rectal cancer patients, reduced the occurrence of postoperative rectal fibrosis, and improved survival and quality of life. This is the first clinical trial to utilize a node-sparing radiation strategy combined with chemotherapy and PD-1 blockade in the neoadjuvant treatment of rectal cancer, which may result in a breakthrough in the treatment of MSS/pMMR rectal cancer. TRIAL REGISTRATION: This study was registered at www. CLINICALTRIALS: gov . TRIAL REGISTRATION NUMBER: NCT05972655. Date of registration: 31 July 2023.

Homologous recombination repair gene mutations in colorectal cancer favors treatment of immune checkpoint inhibitors.

Immune checkpoint inhibitor (ICI) therapy is insensitive for Colorectal cancer (CRC) patients with microsatellite stable (MSS). Genomic data of three CRC cohort, n = 35), and the Cancer Genome Atlas (TCGA CRC cohort, n = 377), were analyzed. A cohort treated with ICIs from Memorial Sloan Kettering Cancer Center (MSKCC CRC cohort, n = 110) and two cases from the local hospital were characterized the impact of the HRR mutation on prognosis of CRC. Homologous recombination repair (HRR) gene mutations were more common in CN and HL cohorts (27.85%; 48.57%) than in TCGA CRC cohort (15.92%), especially in the MSS populations, the frequencies of HRR mutation were higher in CN and HL cohort (27.45%, 51.72%) than in TCGA cohort (6.85%). HRR mutations were associated with high tumor mutational burden (TMB-H). Although HRR mutation uncorrelated with an improved overall survival in the MSKCC CRC cohort (p = 0.97), HRR mutated patients had a significantly improved OS compared to the HRR wildtype population particularly in MSS subgroups (p = 0.0407) under ICI treatment. It probably contributed by a higher neoantigen and increased CD4+ T cell infiltration which found in the TCGA MSS HRR mutated CRC cohort. The similar phenomenon on cases was observed that MSS metastatic CRC patient with HRR mutation seemed more sensitive to ICI after multi-line chemotherapy in clinical practice than HRR wildtype. This finding suggests the feasibility of HRR mutation as an immunotherapy response predictor in MSS CRC, which highlights a potential therapeutic approach for these patients.

Tumor mutation burden is correlated with response and prognosis in microsatellite-stable (MSS) gastric cancer patients undergoing neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NACT) before radical gastrectomy is preferred for locally advanced gastric cancer (GC). However, clinical practices demonstrate that a considerable proportion of GC patients do not benefit from NACT, largely due to the lack of biomarkers for patient selection and prognosis prediction. A recent study revealed that patients with microsatellite instability-high (MSI-H) may be resistant to NACT, however, most tumors in Chinese GC patients (~ 95%) are characterized by microsatellite stability (MSS). Here, we aimed to discover new molecular biomarkers for this larger population. METHODS: We performed whole-exome sequencing on 46 clinical samples (pre- and post-treatment) from 30 stage II/III MSS GC patients whose response to NACT was rigorously defined. Serum tumor markers (TMs), including AFP, CEA, CA199, CA724 and CA242 were measured during the course. RESULTS: High tumor mutation burden (TMB-H) and 19q12 amplification (19q12 +) were positively associated with the NACT response. When TMB and 19q12 amplification were jointly analyzed, those with TMB-H or 19q12 + showed favorable response to NACT (p = 0.035). Further, TMB-H was negatively correlated with ypN stage, lymph node metastasis, and macrophage infiltration. Patients with TMB-H showed better disease-free survival (DFS) than those with TMB-L (P = 0.025, HR = 0.1331), and this was further validated using two larger GC datasets: TCGA-STAD (p = 0.004) and ICGC-CN (p = 0.045). CONCLUSION: The combination of TMB-H and 19q12 + can serve as an early indicator of response to NACT. Superior to traditional clinical indicators, TMB-H is a robust and easily accessible candidate biomarker associated with better DFS, and can be evaluated at the time of diagnosis.

Regorafenib and Nivolumab or Pembrolizumab Combination and Circulating Tumor DNA Response Assessment in Refractory Microsatellite Stable Colorectal Cancer.

BACKGROUND: Metastatic colorectal cancers (MCRCs) with microsatellite stability (MSS) are resistant to immunotherapy with programmed cell death protein 1 (PD-1) and programmed death-ligand 1 inhibitors. However, the addition of regorafenib to nivolumab was recently associated with a high response rate and a protracted progression-free survival in a small cohort of MSS Japanese patients with metastatic colorectal cancer. MATERIALS AND METHODS: We evaluated the outcome of patients with MSS metastatic colorectal cancer who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib in a single U.S. center. RESULTS: A total of 18 patients were treated with a combination of regorafenib and PD-1 inhibitors. No treatment-related grade 3 or above toxicities were noted. Thirteen patients (69%) had progressive disease, and five patients (31%) experienced stable disease as best response. Four out of five stable diseases occurred in patients without liver metastases, whereas only 1 of 14 patients with history of liver metastases had a short disease stabilization. A rise in circulating tumor DNA (ctDNA) at the 4-week time pointuniversally predicted tumor progression at 2 months, whereas a decline was associated with radiographic disease stabilization. CONCLUSIONS: Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant metastatic colorectal cancer. Selection for patients without history of liver metastases may identify a cohort of patients with MSS colorectal cancer with a higher likelihood of benefit from this combination. ctDNA may represent a powerful tool for predicting early therapeutic efficacy of immunotherapy in the MSS colorectal cancer population. IMPLICATIONS FOR PRACTICE: This study showed that the combination of regorafenib and nivolumab was associated with a modest clinical activity in patients with advanced microsatellite stability (MSS) metastatic colorectal cancer. This combination should be avoided in clinical practice, especially in patients with MSS colorectal cancer with liver metastases. Further investigation of regorafenib plus PD-1 inhibitors should be considered in MSS colorectal cancer without liver metastases.

Can reduced field-of-view diffusion sequence help assess microsatellite instability in FIGO stage 1 endometrial cancer?

PURPOSE: To determine if a reduced-field-of-view (rFOV) diffusion intravoxel incoherent motion (IVIM) sequence can differentiate the imaging characteristics of tumors with microsatellite instability (MSI) from those that are microsatellite stable (MSS) in patients with clinical FIGO stage IA endometrial cancer and if MRI can be used to determine MSI status. MATERIALS AND METHODS: Sagittal rFOV diffusion-weighted images were obtained in 12 patients on a 3T scanner using six b-values (0, 50, 100, 150, 200, and 600). These images were used to derive apparent diffusion coefficient (ADC), true diffusion coefficient (Dt ), pseudodiffusion (D*), and perfusion fraction (f). Regions of interest (ROIs) were drawn on the dynamic contrast-enhanced magnetic resonance imaging (MRI) sequence on an Advantage Windows workstation and were copied to the same location on IVIM-derived images. The ROI mean of these images was recorded and compared with the microsatellite status. The depth of myometrial invasion and IVIM-derived parameters were tabulated by microsatellite status. The Wilcoxon rank sum test was used to compare T1 postcontrast images and IVIM-derived images and microsatellite status. RESULTS: Six patients had MSS tumors and six had MSI tumors. MSS tumors had a significantly higher ADC value (P = 0.03) and Dt (P = 0.045) than the MSI tumors. There was no association between < and ≥ 50% depth of myometrial invasion (measured on pathology and MRI analysis) and MSI stability P > 0.99. CONCLUSION: IVIM, ADC and Dt may be able to determine microsatellite status noninvasively in patients with clinical FIGO stage I endometrial cancer. LEVEL OF EVIDENCE: 1 J. Magn. Reson. Imaging 2017;45:1216-1224.

Simvastatin induces ferroptosis and activates anti-tumor immunity to sensitize anti-PD-1 immunotherapy in microsatellite stable gastric cancer.

BACKGROUND: Gastric cancer (GC), especially the case with microsatellite stability (MSS) phenotype, has limited efficacy for immune checkpoint blockade (ICB) therapy. Metabolism reprogramming is newly recognized to affect tumor immune microenvironment (TIME). However, the relationship between metabolism reprogramming and immunotherapy for MSS GC has not been reported. METHODS: A metabolic stratification for GC was developed based on the glycolysis/cholesterol synthesis axis using the R package "ConsensusClusterPlus". The T cell inflamed score was used to define "immune-hot" and "immune-cold" phenotypes in MSS GC. The anti-tumor and immunological effects of simvastatin were explored using in vitro and in vivo experiments. RESULTS: Three metabolic subtypes were identified in GC patients, including cholesterol, glycolysis and quiescent subtypes. The cholesterol subtype was associated with poorer clinical features and higher tumor purity. Correspondingly, we demonstrated that simvastatin, a specific inhibitor of cholesterol synthesis, significantly inhibited the proliferation, migration, and induced ferroptosis in GC cells. Interestingly, simvastatin markedly inhibited tumor growth in immunocompetent mice, while no significant effect in immunodeficient mice. Upregulation of chemokines and increased recruitment of CD8+ T cells were observed after simvastatin treatment. Consistently, the cholesterol subtype exhibited a less inflamed TIME and coincided significantly with the "immune-cold" phenotype of MSS GC. Finally, we confirmed simvastatin enhanced PD-1 blockade efficacy via modulating the TIME and activating anti-tumor immunity in tumor-bearing mice. CONCLUSION: Our data revealed the significance of cholesterol synthesis in GC and demonstrated simvastatin served as a promising sensitizer for ICB therapy by inducing ferroptosis and anti-tumor immunity in MSS GC patients.

Long-term response with the atypical reaction to nivolumab in microsatellite stability metastatic colorectal cancer: A case report.

Immunotherapy has become an integral part of a comprehensive treatment approach to metastatic colorectal cancer (mCRC). Nivolumab (Opdivo) is a human immunoglobulin G4 monoclonal antibody that blocks the interaction between the programmed cell death 1 (PD-1) receptor and its ligands 1/2 (PD-L1/PD-L2), leading to inhibition of T-cell proliferation, cytokine secretion, and enhanced immune response. The US Food and Drug Administration (FDA) has approved this drug for use in high microsatellite instability (MSI-high)/deficiencies in mismatch repair (dMMR) advanced CRC patients. However, its efficacy is extremely limited in microsatellite stability (MSS)/mismatch repair proficient (pMMR) patients. We report a case of a 42-year-old man diagnosed with MSS/pMMR mCRC who has achieved a durable response to nivolumab after a progression under chemotherapy with antiangiogenic treatment. We observed for the first time an atypical response after 8 months of nivolumab treatment, with the regression of previous primary pulmonary lesions and the presence of new para-aortic lymph node lesions. This report demonstrates that a subset of pretreated mCRC patients with the MSS/pMMR phenotype may benefit from nivolumab and these patients need more attention.

Integrative analysis of the immunological significances of guanylate binding protein family genes in microsatellite stability colorectal cancer.

Background: Microsatellite stability (MSS) colorectal cancer (CRC) has poor sensitivity to immunotherapy and its underlying mechanisms are still unclear. Guanylate binding proteins (GBPs) are a family of GTPase involving innate immune responses by providing defense against invading microbes and pathogens. However, the immunological significances of GBPs in MSS CRC remain unknown. Methods: We utilized bioinformatic tools to comprehensively analysis the expression pattern, clinical relevance, prognostic value, biological function, and immunoregulation effect of distinct GBP members in MSS CRC. Results: The expression of all seven GBPs in MSS samples are remarkably decreased compared to microsatellite instability-high (MSI-H) samples. Among them, GBP1/2/4/5 are obviously correlated with distant metastasis status. High expression of GBP1/4/5/6 was remarkably related to favorable overall survival (OS) and progression-free survival (PFS) in CRC patients with MSS tumor. Subsequent enrichment analysis revealed that Interferon-gamma (IFN-γ) and NOD-like receptor signaling are the most relevant functions. Besides, the expression patterns of GBPs are remarkably associated with several tumor infiltrated immune cells (e.g. regulatory T cells, CD4+ T cells, and macrophages) and diverse immunoregulatory molecules (e.g. immune checkpoint biomarkers (ICBs) and major histocompatibility complex (MHC) molecules). Moreover, high GBP1/2/4/5 expression predicted better immunotherapy responsiveness in immunotherapy cohorts. Conclusion: These findings might provide novel insights for the identification of therapeutic targets and potential prognostic biomarkers of GBP family in CRC with MSS samples.

Identification of hub genes and potential molecular mechanisms in MSS/MSI classifier primary colorectal cancer based on multiple datasets.

OBJECTIVE: MSI has a better prognosis than MSS in colorectal cancer patients, and the main objective of this study was to screen for differentially expressed molecules between MSI and MSS primary colorectal cancers using bioinformatics. MATERIAL AND METHODS: Two gene expression datasets (GSE13294 and GSE13067) were downloaded from GEO, and differential expressed genes (DEGs) were analyzed using GEO2R. Gene Ontology, Kyoto Encyclopedia of Genomes, and Gene Set Enrichment Analysis were conducted using the DEGs. Furthermore, a Protein-Protein Interaction Networks (PPI) was constructed to screen for significant modules and identify hub genes. The hub genes were analyzed in colorectal cancer using GEPIA. The expression of hub genes in clinical samples was visualized using the online Human Protein Atlas (HPA). RESULTS: A total of 265 common DEGs were identified in MSS primary colorectal cancer compared to MSI primary colorectal cancer. Among these, 178 DEGs were upregulated, and 87 DEGs were downregulated. Enrichment analysis showed that these DEGs were associated with the response to mechanical stimulus, regulation of cellular response to stress, G protein-coupled receptor binding, and other processes. A total of 5 hub genes was identified by cytoHubba: HNRNPL, RBM39, HNRNPH1, TRA2A, SRSF6. GEPIA software online analysis, 5 hub gene expression in colorectal cancer survival curve did not have significant differences. The expression of RBM39 was significantly different in different stages of colorectal cancer. The HPA online database results showed that the expression of the five hub proteins varied widely in CRC patients. CONCLUSION: The hub genes, such as HNRNPH1and RBM39, and the spliceosome resulting from DEGs, which may provide novel insights and evidence for the future diagnosis and targeted therapy of MSS/MSI PCRC.

Spatial transcriptomic analysis reveals local effects of intratumoral fusobacterial infection on DNA damage and immune signaling in rectal cancer.

Mucinous colorectal cancer (CRC) is a common histological subtype of colorectal adenocarcinoma, associated with a poor response to chemoradiotherapy. The commensal facultative anaerobes fusobacteria, have been associated with poor prognosis specifically in mesenchymal CRC. Interestingly, fusobacterial infection is especially prevalent in mucinous CRC. The objective of this study was therefore to increase our understanding of beneficial and detrimental effects of fusobacterial infection, by contrasting host cell signaling and immune responses in areas of high vs. low infection, using mucinous rectal cancer as a clinically relevant example. We employed spatial transcriptomic profiling of 106 regions of interest from 8 mucinous rectal cancer samples to study gene expression in the epithelial and immune segments across regions of high versus low fusobacterial infection. Fusobacteria high regions were associated with increased oxidative stress, DNA damage, and P53 signaling. Meanwhile regions of low fusobacterial prevalence were characterized by elevated JAK-STAT, Il-17, Il-1, chemokine and TNF signaling. Immune masks within fusobacterial high regions were characterized by elevated proportions of cytotoxic (CD8+) T cells (p = 0.037), natural killer (NK) cells (p < 0.001), B-cells (p < 0.001), and gamma delta T cells (p = 0.003). Meanwhile, fusobacteria low regions were associated with significantly greater M2 macrophage (p < 0.001), fibroblast (p < 0.001), pericyte (p = 0.002), and endothelial (p < 0.001) counts.

Molecular insights into clinical trials for immune checkpoint inhibitors in colorectal cancer: Unravelling challenges and future directions.

Colorectal cancer (CRC) is a complex disease with diverse etiologies and clinical outcomes. Despite considerable progress in development of CRC therapeutics, challenges remain regarding the diagnosis and management of advanced stage metastatic CRC (mCRC). In particular, the five-year survival rate is very low since mCRC is currently rarely curable. Over the past decade, cancer treatment has significantly improved with the introduction of cancer immunotherapies, specifically immune checkpoint inhibitors. Therapies aimed at blocking immune checkpoints such as PD-1, PD-L1, and CTLA-4 target inhibitory pathways of the immune system, and thereby enhance anti-tumor immunity. These therapies thus have shown promising results in many clinical trials alone or in combination. The efficacy and safety of immunotherapy, either alone or in combination with CRC, have been investigated in several clinical trials. Clinical trials, including KEYNOTE-164 and CheckMate 142, have led to Food and Drug Administration approval of the PD-1 inhibitors pembrolizumab and nivolumab, respectively, for the treatment of patients with unresectable or metastatic microsatellite instability-high or deficient mismatch repair CRC. Unfortunately, these drugs benefit only a small percentage of patients, with the benefits of immunotherapy remaining elusive for the vast majority of CRC patients. To this end, primary and secondary resistance to immunotherapy remains a significant issue, and further research is necessary to optimize the use of immunotherapy in CRC and identify biomarkers to predict the response. This review provides a comprehensive overview of the clinical trials involving immune checkpoint inhibitors in CRC. The underlying rationale, challenges faced, and potential future steps to improve the prognosis and enhance the likelihood of successful trials in this field are discussed.

Shaping immune landscape of colorectal cancer by cholesterol metabolites.

Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.

Application of sintilimab combined with anlotinib hydrochloride in the clinical treatment of microsatellite stable colorectal cancer.

BACKGROUND: Microsatellite stable (MSS) colorectal cancer (CRC) is a common type of tumor with limited treatment options. Sintilimab and anlotinib hydrochloride are two extensively studied anticancer drugs. AIM: To probe the clinical value of combining sintilimab with anlotinib hydrochloride in MSS CRC treatment. METHODS: During the period spanning from April 2019 to April 2022, Zhejiang Provincial People's Hospital accommodated a cohort of 92 patients diagnosed with MSS CRC who were classified into two distinct groups in our study, the observation group and the control group. The control group was administered anlotinib hydrochloride as their designated therapy, whereas the observation group received the additional treatment of sintilimab in conjunction with the therapy assigned to the control group. The administration of treatment occurred in cycles consisting of a duration of 3 wk, and the evaluation of effectiveness took place subsequent to the completion of two consecutive cycles of treatment within both groups. A comparative analysis between the two groups was conducted to assess the short-term efficacy and ascertain the incidence of adverse events transpiring throughout the duration of the treatment period. Changes in the levels of carcinoembryonic antigen, carbohydrate antigen 199 (CA199), CA125, and T cell subsets (CD4+, CD8+, CD4+/CD8+) as well as the assessment of the quality of life using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 were compared between the two groups prior to and subsequent to therapy. Finally, a 1-year follow-up was conducted for both groups of patients, and the survival status was recorded and analyzed. RESULTS: The short-term effectiveness displayed by the observation group surpassed that exhibited by the control group, with a statistically significant discrepancy (76.09% vs 50.00%), reaching a significance level denoted as P < 0.05. Following the administration of treatment, the observation group manifested a considerable reduction in numerous serum indicators, which were found to be lower than the corresponding pretreatment levels within the same group as well as the post-treatment levels observed in the control group (P < 0.05). Post-treatment, the T lymphocyte subset levels within the observation group demonstrated a remarkable amelioration, surpassing the corresponding pre-treatment levels observed within the same group as well as the post-treatment levels observed in the control group (P < 0.05). Subsequent to the therapeutic intervention, the observation group showcased a notable amelioration in the scores associated with multiple dimensions of life quality. These scores outperformed the pretreatment scores within the same group as well as the post-treatment scores observed in the control group (P < 0.05). The safety levels of drug use in the two group were comparable (19.57% vs 13.04%), and no distinct difference was observed upon comparison (P > 0.05). After the completion of treatment, both groups of patients underwent a 1-year follow-up outside the hospital. Throughout this period, 1 patient within the observation group and 2 patients within the control group became untraceable and were lost to follow-up. During the follow-up period of the observation group, 12 patients died, resulting in a survival rate of 73.33% (33/45), while in the control group, 21 patients died, resulting in a survival rate of 52.27% (23/44). The implementation of Kaplan-Meier survival analysis revealed a conspicuous contrast in survival rates exhibited by the two groups (log-rank = 4.710, P = 0.030). CONCLUSION: The combination of sintilimab and anlotinib hydrochloride demonstrated favorable efficacy in the treatment of MSS CRC patients, leading to improvements in patient immunity and prognosis. Additionally, it exerted inhibitory effects on the expression of carcinoembryonic antigen, CA199, and CA125.

Identification of the molecular characteristics associated with microsatellite status of colorectal cancer patients for the clinical application of immunotherapy.

Background: Mismatch repair-proficient (pMMR) microsatellite stability (MSS) in colorectal cancer (CRC) indicates an unfavorable therapeutic response to immunotherapy with immune checkpoint inhibitors (ICIs). However, the molecular characteristics of CRC patients with pMMR MSS remain largely unknown. Methods: Heterogeneities between mismatch repair-deficient (dMMR) microsatellite instability (MSI) and pMMR MSS CRC patients were investigated at the single-cell level. Next, an MSS-related risk score was constructed by single-sample gene set enrichment analysis (ssGSEA). The differences in immune and functional characteristics between the high- and low-score groups were systematically analyzed. Results: Based on the single-cell RNA (scRNA) atlas, an MSS-specific cancer cell subpopulation was identified. By taking the intersection of the significant differentially expressed genes (DEGs) between different cancer cell subtypes of the single-cell training and validation cohorts, 29 MSS-specific cancer cell marker genes were screened out for the construction of the MSS-related risk score. This risk score signature could efficiently separate pMMR MSS CRC patients into two subtypes with significantly different immune characteristics. The interactions among the different cell types were stronger in the MSS group than in the MSI group, especially for the outgoing signals of the cancer cells. In addition, functional differences between the high- and low-score groups were preliminarily investigated. Conclusion: In this study, we constructed an effective risk model to classify pMMR MSS CRC patients into two completely different groups based on the specific genes identified by single-cell analysis to identify potential CRC patients sensitive to immunotherapy and screen effective synergistic targets.

Long-term response to sintilimab, bevacizumab and chemotherapy in heavily pretreated microsatellite stable colon cancer.

Most advanced colorectal cancer patients with proficient DNA mismatch repair or microsatellite stability (MSS) are insensitive to immune checkpoint inhibitor therapy. This report describes a heavily pretreated refractory colon adenocarcinoma patient with MSS. After experiencing four lines of treatment, the patient received the fifth-line therapy with the combined sintilimab, bevacizumab and chemotherapy. She achieved a long-term clinical outcome. The patient's progression-free survival after the fifth-line therapy was approximately 9.3 months, and her overall survival was approximately 57 months. To the best of our knowledge, this case represents the first report of durable clinical benefit from combination of an immune checkpoint inhibitor, bevacizumab and chemotherapy in a heavily pretreated patient with refractory metastatic colon adenocarcinoma with MSS.

To date, little information is available on the efficacy of combination of immunotherapy, antiangiogenic therapy and chemotherapy in heavily pretreated refractory colon cancer patients with microsatellite stability (MSS). Here, we describe a heavily pretreated refractory colon adenocarcinoma patient with MSS. After experiencing four lines of prior treatment, the patient received the fifth-line therapy with the combined immunotherapy, an antiangiogenetic inhibitor and chemotherapy. She achieved a durable clinical outcome. To our knowledge, this case is the first report of successful treatment of a heavily pretreated refractory metastatic colon adenocarcinoma patient with MSS receiving the combined immunotherapy, antiangiogenic therapy and chemotherapy.

A Case of Complete Remission in Proficient Mismatch Repair (pMMR) Advanced Colon Cancer Treated with Sintilimab and XELOX.

Introduction: Colorectal cancer (CRC) is the 3rd most common malignant tumors after breast cancer and lung cancer, accounting for 9.4% of patients. Some patients had distant metastasis at the time of diagnosis without surgery opportunity. It is particularly important to prolong patient survival and improve quality of life. Patient Concerns: A 73-year-old female was admitted with discomfort over 2 months. Enlarged lymph nodes in the left supraclavicular fossa were observed in chest computed tomography (CT). Enhanced abdominal CT showed thickening of the right colon wall with multiple metastatic lymph nodes in the abdomen. Colonoscopy showed ileocecal mass and pathology showed moderately and poorly differentiated adenocarcinoma. Physical examination showed a 2*2 cm lymph node could be touched in the left supraclavicular fossa. The patient was diagnosed advanced colon cancer by the histopathological examination and imaging findings. Actually, it is hardly to resect radically. Intervention: Sintilimab combined with XELOX was initiated. Two period of treatment after initial therapy, laparoscopic radical resection of right colon cancer was performed successfully. Outcomes: After conversion treatment, the enlarged lymph nodes and primary tumor were significantly reduced. The patient was discharged successfully three weeks after surgery. Both specimen and 14 lymph nodes dissected showed no malignancy in pathology. Tumor regression grading (TRG) is 0, which indicate complete regression with no residual tumor cells including lymph nodes. The patient obtained a pathological complete response (pCR). Lessons: The patient achieved a great therapeutic benefit with the above-mentioned chemotherapy in this case. The case provides a potential reference for pMMR CRC patients treating with immune checkpoint inhibitors (ICIs).

Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era?

Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.

Metastatic Colorectal Cancer Patient with Microsatellite Stability and Germline BRAC2 Mutation Shows a Complete Response to Olaparib in Combination with a PD-1 Inhibitor and Bevacizumab: A Case Report and Review of the Literature.

Metastatic colorectal cancer (mCRC) has a poor prognosis. Combining chemotherapy with targeted therapy constitutes a basic form of mCRC treatment. Immune checkpoint inhibitors have been recommended for microsatellite instability mCRC, while most patients harboring microsatellite stability (MSS) or proficient mismatch repair (pMMR) are less responsive to immunotherapy. Combinational targeted therapy, including poly-ADP ribose polymerase (PARP) inhibitors, has been considered a promising way to reverse immunotherapy resistance; however, there is no clear and consistent conclusions can be drawn from the current research. Here, we report the case of a 59-year-old woman diagnosed with stage IVB MSS mCRC who received three courses of capecitabine/oxaliplatin chemotherapy combined with bevacizumab as a first-line treatment, resulting in an overall evaluation of stable disease (-25.7%). However, the occurrence of adverse events of intolerable grade 3 diarrhea and vomiting forced the cessation of this therapy. A germline BRCA2 mutation was found by next-generation sequencing, and the patient further received a combination of olaparib, tislelizumab, and bevacizumab. This treatment regime resulted in a complete metabolic response and a partial response (-50.9%) after 3 months of treatment. Mild asymptomatic interstitial pneumonia and manageable hematologic toxicity were two adverse events associated with this combination therapy. This study provides new insights into the combination of PARP inhibitors and immunotherapy for MSS mCRC patients carrying germline BRCA2 mutations.