KMT2C as a positive predictor for treatment of immune checkpoint inhibitor and correlation with immune infiltrates in colorectal cancer (CRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3538-3538
Author(s):  
Ling Zhang ◽  
Jianping Song ◽  
Yiting Wang ◽  
Yaoxu Chen
Keyword(s):  
Colorectal Cancer ◽  
Survival Data ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Colon Adenocarcinoma ◽  
Treg Cells ◽  
Prognostic Effect

3538 Background: Lysine Methyltransferase 2C (KMT2C), a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family, possesses histone methylation activity and is involved in transcriptional co-activation. Present study has shown that KMT2C is positive correlated with better efficacy of Immune checkpoint inhibitor (ICI) in NSCLC. However, the role of KMT2C in treatment of ICI on colorectal cancer (CRC) is still unknown. Methods: NGS (Next Generation Sequencing) was performed on 1628 CRC patients. TMB of these patients were analyzed. A public accessible cohort (Samstein2018) with data from 130 CRC patients were used to investigate the correlation between KMT2C mutation and efficacy of ICI. WES and survival data of TCGA database (1099 CRC) was used to analyze prognostic effect of KMT2C mutation. Furthermore, CIBERSORT was used to analyze the tumor-infiltrating immune cells present in COAD（colon adenocarcinoma, 404 patients）from TCGA database. Results: Among 1628 CRC patient, 230(14.1%) had KMT2C mutation. TMB was positive correlated with KMT2C mutation (Mut vs. WT, 30.75 vs. 7.26 mut/Mb, p < 0.0001). The Samstein2018 cohort showed that KMT2C mutations (15.4%, 20/130) were significantly associated with better OS (Mut vs. WT, 11.5 vs. 7.5 month, HR = 0.29; 95% CI, 0.1-0.81; P = 0.012), and a higher TMB was also observed in KMT2C-Mut group (p = 1.98e-08). In TCGA, no association between KMT2C mutation and OS was observed (P = 0.23), suggesting that was not prognostic factor. Moreover, we analyzed the relationship between KMT2C mutation and immune cell infiltration through CRC TCGA database. The results showed, in COAD, KMT2C mutation was positively correlated with the abundance of CD8+ T cells (P = 0.0014), B cells (P = 0.014), M1 macrophages (P = 0.015), neutrophil (P = 0.0019) and NK cells (P = 0.043), and negatively correlated with Treg cells (p = 0.0063). Conclusions: KMT2C has an impact on the immune microenvironment and may be used as a potential positive predictor for treatment of ICI on CRC patients. The role of KMT2C in immunotherapy warrant further studies.

scholarly journals Cancer Immune Checkpoint Inhibitor Therapy and the Gut Microbiota

2019 ◽  
Vol 18 ◽  
pp. 153473541984637 ◽  
Author(s):  
Arthur E. Frankel ◽  
Sachin Deshmukh ◽  
Amit Reddy ◽  
John Lightcap ◽  
Maureen Hayes ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Host Immune System ◽  
The Past ◽  
Checkpoint Inhibitor Therapy ◽  
Gut Microbial Community ◽  
Generation Sequencing

The past decade has seen tremendous advances in both our understanding of cancer immunosuppressive microenvironments and colonic bacteria facilitated by immune checkpoint inhibitor antibodies and next generation sequencing, respectively. Because an important role of the host immune system is to communicate with and regulate the gut microbial community, it should not come as a surprise that the behavior of one is coupled to the other. In this review, we will attempt to dissect some of the studies demonstrating cancer immunotherapy modulation by specific gut microbes and discuss possible molecular mechanisms for this effect.

scholarly journals Emerging Role of Vedolizumab in Managing Refractory Immune Checkpoint Inhibitor-Induced Enteritis

2018 ◽  
Vol 5 (1) ◽  
pp. e17 ◽  
Author(s):  
Pietro Diana ◽  
Charoen Mankongpaisarnrung ◽  
Michael B. Atkins ◽  
Jay C. Zeck ◽  
Aline Charabaty
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor

scholarly journals Analysis of Tumor Microenvironment Characteristics in Bladder Cancer: Implications for Immune Checkpoint Inhibitor Therapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xingyu Chen ◽  
Haotian Chen ◽  
Dong He ◽  
Yaxin Cheng ◽  
Yuxing Zhu ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Cox Regression ◽  
Prognostic Biomarker ◽  
Checkpoint Inhibitor ◽  
Clinical Prognosis

The tumor microenvironment (TME) plays a crucial role in cancer progression and recent evidence has clarified its clinical significance in predicting outcomes and efficacy. However, there are no studies on the systematic analysis of TME characteristics in bladder cancer. In this study, we comprehensively evaluated the TME invasion pattern of bladder cancer in 1,889 patients, defined three different TME phenotypes, and found that different subtypes were associated with the clinical prognosis and pathological characteristics of bladder cancer. We further explored the signaling pathways, cancer-immunity cycle, copy number, and somatic mutation differences among the different subtypes and used the principal component analysis algorithm to calculate the immune cell (IC) score, a tool for comprehensive evaluation of TME. Univariate and multivariate Cox regression analyses showed that ICscore is a reliable and independent prognostic biomarker. In addition, the use of anti-programmed death-ligand (PD-L1) treatment cohort, receiver operating characteristic (ROC) curve, Tumor Immune Dysfunction and Exclusion (TIDE), Subnetwork Mappings in Alignment of Pathways (SubMAP), and other algorithms confirmed that ICscore is a reliable prognostic biomarker for immune checkpoint inhibitor response. Patients with higher ICscore showed a significant therapeutic advantage in immunotherapy. In conclusion, this study improves our understanding of the characteristics of TME infiltration in bladder cancer and provides guidance for more effective personalized immunotherapy strategies.

scholarly journals Molecular profiling of signet ring cell colorectal cancer provides a strong rationale for genomic targeted and immune checkpoint inhibitor therapies

2017 ◽  
Vol 117 (2) ◽  
pp. 203-209 ◽  
Author(s):  
Muhammad A Alvi ◽  
Maurice B Loughrey ◽  
Philip Dunne ◽  
Stephen McQuaid ◽  
Richard Turkington ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Molecular Profiling ◽  
Signet Ring Cell ◽  
Signet Ring ◽  
Ring Cell

Outcomes in patients with advanced non-small cell lung cancer (aNSCLC) and high PD-L1 expression treated with immune checkpoint inhibitor monotherapy: An FDA-pooled analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9606-9606
Author(s):  
Sujay Yogesh Shah ◽  
Jonathon Joseph Vallejo ◽  
Yutao Gong ◽  
Thomas D. Brown ◽  
Chenan Zhang ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Cell ◽  
Checkpoint Inhibitor ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Cell Staining ◽  
Line Of Therapy ◽  
The Relationship

9606 Background: Higher PD-L1 score ≥ 50% predicts for greater benefit to immune checkpoint inhibitor (ICI) therapy in first line (1L) treatment of aNSCLC. It has recently been reported that PD-L1 score ≥ 90% predicts for even greater benefit to 1L ICI monotherapy (Aguilar et al., 2019). We examined pooled clinical trial databases to examine the relationship between high PD-L1 expression across multiple ICI monotherapies in 1L and second line (2L) treatment of aNSCLC. Methods: Data was pooled from trials (five 1L and five 2L) of ICI for the treatment of patients with aNSCLC. We defined PD-L1 score as the proportion of tumor cell stained by the assay (total of four assays identified) and included patients in the analysis with PD-L1 score ≥ 50%. Tumor-infiltrating immune cell staining was not considered. Progression-free survival (PFS) and overall survival (OS) by line of therapy for patients with PD-L1 score ≥ 90% and patients with PD-L1 score 50-89% was analyzed. Results: A total of 1320 patients treated with ICI monotherapy were identified, 873 in 1L and 447 in 2L. Median follow-up was 9.6 months in 2L patients and 13.3 months in 1L patients. Patients receiving 2L ICI therapy with PD-L1 score ≥ 90% (N = 208) had longer PFS and OS compared to patients with PD-L1 score 50-89% (N = 239), with mPFS 7.1 vs. 4.2 months (HR = 0.66 [95% CI: 0.52-0.83]) and mOS NR vs. 15.8 months (HR = 0.66 [95% CI: 0.49-0.89]). 1L ICI therapy analysis revealed similar trends, as patients with PD-L1 score ≥ 90% (N = 405) had longer PFS and OS compared to patients with a PD-L1 score 50-89% (N = 468), with mPFS 8.3 vs. 5.4 months (HR = 0.78 [95% CI: 0.66-0.92]) and mOS 22.9 vs. 16.4 months (HR = 0.74 [95% CI: 0.61-0.90]). Conclusions: This analysis showed the potential of an enhanced clinical benefit in patients with aNSCLC and PD-L1 score ≥90% across ICI monotherapies in both the 1L and 2L treatment setting. These data will be further analyzed in real world populations.

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