Correlation between driver mutation and immune microenvironment in colorectal cancer patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15513-e15513
Author(s):  
Xiaochen Cai ◽  
Yuezong Bai ◽  
Xiaochen Zhao ◽  
Longgang Cui ◽  
Hui Chen
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Nk Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Braf Mutation ◽  
Kras Mutation ◽  
Tumor Stroma ◽  
Wild Type ◽  
Colorectal Cancer Patients

e15513 Background: Immune checkpoint inhibitor (ICI) therapy has made great achievements, but ICI monotherapies show less effectiveness in colorectal cancer patients. Biomarker exploration have carried out from PD-L1 expression, neo-antigen, gene mutation, etc., but no satisfactory results have been obtained. Methods: Patients, Colorectal cancer patients. Methods, Multi-color immunohistochemistry (multi-IHC) was used to evaluate CD8+ T cells, macrophages and natural killer cell (NK cell) in tumors and tumor stroma. The Shapiro-Wilk method was used to test the normality of the data, and the t-test or Mann-Whitney U test was used according to the test results. A two-sided P < 0.05 was considered a significant difference. Results: The study included 72 colorectal cancer patients, including 26 female (36.7%) and 46 male (63.8%), with a median age of 59.5 (50-67.3). There were 6 patients (8.3%) with BRAF mutation, 43 patients (59.7%) with KRAS mutation, and 56 patients (77.8%) with TP53 mutation. The results of immunohistochemistry showed that, BRAF mutation Vs BRAF wild-type or KRAS mutation Vs KRAS wild-type, the number or proportion of CD8+ T cells, macrophages or NK cells in tumor and tumor stroma were not statistically different. For TP53 mutation Vs TP53 wild-type, the number and proportion of CD8+ T cells or macrophages in tumor and tumor stroma were not statistically different. There was no statistical difference in the number and proportion of NK cells in tumor. But, the median number of NK cells in tumor stroma was 345 Vs 129, p = 0.06, and the proportion of NK cells was 5.2% Vs 1.39%, p = 0.02. Conclusions: There is no significant change in the immune microenvironment of colorectal cancer patients with BRAF mutation and KRAS mutation. There are more NK cells in tumor stroma of colorectal cancer patients with TP3 mutation.

KRAS mutation profile in colorectal cancer patients in Brazil: A cohort of 989 individuals

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15017-e15017
Author(s):  
M. G. Zalis ◽  
F. M. Vieira ◽  
I. Zalcberg-Renault ◽  
M. H. Bonamino ◽  
C. G. Ferreira ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Kras Mutation ◽  
Genetic Background ◽  
Brazilian Population ◽  
Wild Type ◽  
Asian Populations ◽  
Mutation Profile ◽  
Significant Difference ◽  
Colorectal Cancer Patients

e15017 Background: KRAS mutation is common event in colorectal cancer occurring in around 40% of the patients. It is well- known that patients harboring the KRAS mutation do not derive benefit from cetuximab. However data available KRAS mutation profile is limited to Caucasian and Asian individuals and there is a lack of data in the population from Latin America. Brazilian population has a heterogeneous genetic background and this may have pharmacogenetic implications (Suarez-Kurtz, 2006). Methods: Between July and November 2008, we analyzed 989 consecutive patient samples sent to our laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exons 1 were amplified by PCR and submitted to automatic sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and 53% of the patients were male and 47% female. The percentage of wild-type and mutated KRAS was 62 and 38%, respectively. Among the 375 mutated cases, 87% were in codon 12 versus 13% in codon 13. Mutation Gly12Asp was the most common being detected in 39% of the mutated cases. Due to the sample size a comparison among patients from different regions of Brazil was possible. However, no significant difference was observed in relation to the type or percentage of patients harboring the KRAS mutation. Interestingly, a significant difference in the percentage of mutated KRAS patients was observed between male and female (41 versus 35%, p= 0.05). Conclusions: The profile of KRAS mutation in the Brazilian population is similar to that reported for Caucasian and Asian populations. This is one of the largest cohorts of KRAS genotyping in colorectal cancer patients ever reported. To the best of our knowledge our data is the first to put forward the issue of a potential difference in the mutation rate according to gender. The observed higher incidence of KRAS-mutation in male than female deserves further investigation. No significant financial relationships to disclose.

Predictive value of ERCC1 and KRAS in colorectal cancer patients with FOLFOX chemotherapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 588-588
Author(s):  
In Kyu Lee ◽  
Sung-Bong Choi ◽  
DaeYoung Cheung ◽  
Jin Il Kim
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Kras Mutation ◽  
Disease Free Survival ◽  
Wild Type ◽  
Free Survival ◽  
Significant Difference ◽  
Colorectal Cancer Patients ◽  
Disease Free

588 Background: To determine the clinical significance of KRAS mutation and ERCC1 overexpression as a predictive factor of resistance in oxaliplatin based treatment. Methods: We retrospectively analyzed the clinicopathologic features, status of KRAS mutation and ERCC1 overexpression of 386 colorectal cancer patients who received curative intent surgery. Among them 84 patients were treated by FOLFOX regimen as the first line. Their disease-free survival and overall survival according to the KRAS and ERCC1 were analyzed. Results: About a quarter of patients (25.5%) were represented KRAS wild type with ERCC1 overexpression. Among the patients who treated by FOLFOX regimen, 73 patients were evaluated both of the KRAS and ERCC1. There were no significant differences of disease-free survival and overall survival according to KRAS status and ERCC1 expression each. Under the subgroup analysis, overall survival of ERCC1 overexpression group in wild type KRAS was poor than ERCC1 negative group (p=.029), but no significant difference was in mutant KRAS group (p=.671). Conclusions: Our results suggest that the KRAS wild type with ERCC1 overexpression would be associated with the resistance of oxaliplatin.If oxaliplatin based chemotherapy would beconsidered, status of KRAS mutation and ERCC1 overexpression should be evaluated.

scholarly journals Distinct epigenetic features of tumor-reactive CD8+ T cells in colorectal cancer patients revealed by genome-wide DNA methylation analysis

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Rui Yang ◽  
Sijin Cheng ◽  
Nan Luo ◽  
Ranran Gao ◽  
Kezhuo Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Methylation ◽  
T Cells ◽  
T Cell ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Methylation Status ◽  
Effector Memory ◽  
Binding Motif ◽  
Colorectal Cancer Patients

Abstract Background Tumor-reactive CD8+ tumor-infiltrating lymphocytes (TILs) represent a subtype of T cells that can recognize and destroy tumor specifically. Understanding the regulatory mechanism of tumor-reactive CD8+ T cells has important therapeutic implications. Yet the DNA methylation status of this T cell subtype has not been elucidated. Results In this study, we segregate tumor-reactive and bystander CD8+ TILs, as well as naïve and effector memory CD8+ T cell subtypes as controls from colorectal cancer patients, to compare their transcriptome and methylome characteristics. Transcriptome profiling confirms previous conclusions that tumor-reactive TILs have an exhausted tissue-resident memory signature. Whole-genome methylation profiling identifies a distinct methylome pattern of tumor-reactive CD8+ T cells, with tumor-reactive markers CD39 and CD103 being specifically demethylated. In addition, dynamic changes are observed during the transition of naïve T cells into tumor-reactive CD8+ T cells. Transcription factor binding motif enrichment analysis identifies several immune-related transcription factors, including three exhaustion-related genes (NR4A1, BATF, and EGR2) and VDR, which potentially play an important regulatory role in tumor-reactive CD8+ T cells. Conclusion Our study supports the involvement of DNA methylation in shaping tumor-reactive and bystander CD8+ TILs, and provides a valuable resource for the development of novel DNA methylation markers and future therapeutics.

scholarly journals Clinical characteristics and prognostic value of the KRAS mutation in Chinese colorectal cancer patients

2021 ◽  
pp. 172460082110171
Author(s):  
Ye Yuan ◽  
Yingting Liu ◽  
Ye Wu ◽  
Junling Zhang ◽  
Chunti Shen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
High Frequency ◽  
Kras Mutation ◽  
Chinese Patients ◽  
Wild Type ◽  
Kras Mutations ◽  
Exon 2 ◽  
Colorectal Cancer Patients

Background: The KRAS mutations are high-frequency somatic mutations found in colorectal cancer patients from Western and Asian countries however, with the exception of exon 2 of KRAS, other prevalence and prognostic values have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of whole exon mutations of KRAS in Chinese colorectal cancer patients and to investigate their impact on prognosis. Methods: A total of 7189 tumor tissue samples (iCohort) were subjected to next-generation sequencing for detection of KRAS mutations. All pathologic or likely pathologic mutations of KRAS were considered. In addition, clinical features and prognostic dates were collected from 145 patients at The Third Affiliated Hospital of Soochow University, China (sCohort) and used droplet digital™ polymerase chain reaction to detect KRAS mutations. Results: In the iCohort, 2706 patients (37.6%) were confirmed harboring KRAS mutations. The most frequent of these mutations were G12D (32.19%), G12V (17.96%), and G13D (17.59%). In the sCohort, 51 colorectal cancer patients (35.17%) had KRAS mutations, among which KRAS G12D (64.71%), G13D (29.41%), and G14D (3.92%) were high-frequency. The KRAS mutations were associated with shorter median overall survival than wild-type tumors (69 vs. 55 months; HR 1.80; 95% Cl 1.22, 2.64; P=0.0003). In the Cox multivariate analysis, age (HR 1.562; 95% Cl 1.10, 2.22; P=0.013), tumor differentiation (HR 0.417; 95% Cl 0.19, 0.90; P=0.026), and KRAS mutation (HR 1.897; 95% Cl 0.19, 0.90; P=0.001) remained independent predictors of shorter overall survival. Among the common KRAS mutations, G12D was significantly associated with shorter overall survival (HR 2.17; 95% Cl 1.31, 3.58; P < 0.0001) compared with KRAS wild-type patients. Conclusions: Our findings indicate that KRAS genes are frequently mutated, and over 30% harbored the KRAS G12D mutation subtype. We found that the KRAS G12D mutation is associated with inferior survival and is a biomarker of poor prognosis in Chinese patients. Our data emphasize the importance of molecular features in colorectal cancer patients, which could potentially be improved by G12D-specific related inhibitors.

scholarly journals Correlation between emotional regulation and peripheral lymphocyte counts in colorectal cancer patients

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9475
Author(s):  
Estela Kakoo Brioso ◽  
Sérgio Ferreira Cristina ◽  
Luis Costa ◽  
Silvia Ouakinin
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Nk Cells ◽  
Cancer Patients ◽  
Nk Cell ◽  
Trait Anger ◽  
Longitudinal Assessment ◽  
Cell Counts ◽  
Colorectal Cancer Patients

Background Colorectal cancer is one of the most common cancers worldwide. Psychological morbidity has an important impact on quality of life and major clinical outcomes. Several data have shown that the immune system may be a key player on the relation between psychological features and cancer outcomes. Natural Killer (NK) cells have been shown to be influenced by psychological factors. The aim of this investigation was to assess the impact of anxiety, depression, and anger state, trait, and expression on the immune response, particularly, their effect on NK cells and CD8+ T cells in surgical colorectal cancer patients. Methods We studied 54 surgical colorectal cancer patients and assessed patients pre-surgically, post-surgically, and 12 months after surgery (follow-up). We applied the Hospital Anxiety and Depression Scale and the State-Trait Anger Expression Inventory and measured peripheral T cells, CD8+ T cells, and NK cells. We did a cross-sectional analysis as well as a longitudinal assessment of the variables during the follow-up period. Results Pre-surgical assessment: Trait anger, angry reaction, and anger-out had a significant negative correlation with NK cells. The lymphocytes values were unaffected by the presence of clinical anxiety or depression. Post-surgical assessment: Patients without clinical anxiety had higher levels of T cells. Angry reaction was negatively correlated with NK cells. Lymphocytes values were unaffected by the presence of clinical depression. Follow-up assessment: Patients without clinical depression had higher T cell counts. Trait anger and angry reaction were negatively correlated with the levels of NK cells. The lymphocytes values were unaffected by the presence of clinical anxiety. Longitudinal assessment: Angry-temperament, anger expression, and anger-in reduced significantly from the first to the second assessment. Anxiety, state anger, and trait anger significantly diminished from the pre-surgical to the follow-up assessment. Depression levels did not alter during the follow-up period. The lymphocyte count, and particularly T cells and CD8+ T cells, was significantly higher in the follow-up when compared with the pre-surgical assessment. Conclusion Our study suggests the existence of a relation between psychological response and immune response in colorectal cancer patients. We identified the importance of emotional regulation as a potential modulator for NK cell counts. Higher values of propensity to experience anger states and express them outwards seem to be associated with lower NK cell counts.

scholarly journals KRAS mutation analysis: a comparison between primary tumours and matched liver metastases in 305 colorectal cancer patients

2011 ◽  
Vol 104 (6) ◽  
pp. 1020-1026 ◽  
Author(s):  
N Knijn ◽  
L J M Mekenkamp ◽  
M Klomp ◽  
M E Vink-Börger ◽  
J Tol ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Cancer Patients ◽  
Mutation Analysis ◽  
Kras Mutation ◽  
Colorectal Cancer Patients

Novel CoupledCAR technology for treating colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2528-2528
Author(s):  
Lei Xiao ◽  
Song Li ◽  
Chengfei Pu ◽  
Zhiyuan Cao ◽  
Xinyi Yang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
Complete Remission ◽  
Cancer Patients ◽  
Solid Tumors ◽  
Tumor Tissue ◽  
Lentiviral Vectors ◽  
Safety And Efficacy ◽  
Pet Ct ◽  
Colorectal Cancer Patients

2528 Background: Chimeric antigen receptor (CAR) T cell therapy has made significant progress in the treatment of blood cancers such as leukemia, lymphoma, and myeloma. However, the therapy faces many challenges in treating solid tumors. These challenges include physical barriers, tumor microenvironment immunosuppression, tumor heterogeneity, target specificity, and limited expansion in vivo. Methods: We designed a CAR lentivirus vector that consisted of a humanized CD19-specific single-chain variable fragment (scFv), a 4-1BB costimulatory domain, and a CD3ζ signaling domain.The lentivirus was produced by transfecting HEK-293T cells with CAR lentiviral vectors and viral packaging plasmids. Patient’s CD3 T cells was cultured in X-VIVO medium containing 125U/mL 1interleukin-2 (IL-2), and transduced with CAR lentivirus at certain MOI 24h after stimulated by anti-CD3/CD28 magnetic beads. Transduction efficiency was evaluated at 7 to 9 days after CAR lentivirus transduction, and quality controls for fungi, bacteria, mycoplasma, chlamydia, and endotoxin were performed. After infusion, serial peripheral blood samples were collected, and the expansion and the cytokine release of CART cells were detected by FACS and QPCR,respectively. The evaluation of response level for patients were performed at month 1,month 3,and month 6 by PET/CT. Results: We engineered CoupledCAR T cells with lentiviral vectors encoding an anti-GCC (guanylate cyclase 2C) CAR molecule. To verify the safety and efficacy of CoupledCAR-T cells for treating solid tumors, we conducted several clinical trials for different solid tumors, including seven patients with colorectal cancer. These seven patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the metastatic colorectal cancer patients were infused with autologous anti-GCC CoupledCAR-T cells range from 4.9×105/kg to 2.9×106/kg. We observed that CoupledCAR-T cells expanded significantly in the patients and infiltrated tumor tissue sites, demonstrating enhanced anti-tumor activities. PET/CT showed significant tumor shrinkage and SUV max declined, and the ongoing responses were monitored. Patient 3 achieved complete response and the best overall response rate (ORR, include complete remission, complete metabolic response, and partial response.) was 57.1% (4/7), complete remission (CR) rate was 14.3% (1/7). Conclusions: In conclusion, the clinical data demonstrated that CoupledCAR-T cells effectively expanded, infiltrated tumor tissue sites, and kill tumor cells in patients with colorectal cancer. We used immunotherapy to achieve complete remission in patients with advanced colorectal cancer for the first time. We are recruiting more colorectal cancer patients to further test the safety and efficacy of anti-GCC CoupledCAR T cells. Since our CoupledCAR technology is a platform technology, we are expanding it to treat other solid tumors using different target tumor markers.

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