scholarly journals Prediction of Benefit from Checkpoint Inhibitors in Mismatch Repair Deficient Metastatic Colorectal Cancer: Role of Tumor Infiltrating Lymphocytes

2020 ◽  
Vol 25 (6) ◽  
pp. 481-487 ◽  
Author(s):  
Fotios Loupakis ◽  
Ilaria Depetris ◽  
Paola Biason ◽  
Rossana Intini ◽  
Alessandra Anna Prete ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Infiltrating Lymphocytes

scholarly journals Role of the Pathologist in the Diagnosis of Hereditary Non-Polyposis Colorectal Cancer

2004 ◽  
Vol 20 (4-5) ◽  
pp. 215-224 ◽  
Author(s):  
Jeremy R. Jass
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Tumor Infiltrating Lymphocytes ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Dna Mismatch Repair Genes ◽  
Histological Criteria ◽  
Dna Microsatellite ◽  
Infiltrating Lymphocytes

The aim of this paper is to indicate how the pathologist may suspect a diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) on the basis of histological criteria and patient age alone. A single morphological feature, namely the presence of intra-epithelial lymphocytes (tumor infiltrating lymphocytes), identifies the majority of colorectal cancers (CRC) with the DNA microsatellite instability-high phenotype. A number of pathological criteria can help to distinguish HNPCC from sporadic MSI-H CRC, though age below 60 years is an important pointer towards HNPCC. Immunohistochemistry to demonstrate loss of expression of DNA mismatch repair genes serves as a highly reliable test of mismatch repair deficiency if antibodies to hMLH1, hMSH2, hMSH6 and hPMS2 are employed.

scholarly journals Immunotherapy in Metastatic Colorectal Cancer: Could the Latest Developments Hold the Key to Improving Patient Survival?

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 889 ◽  
Author(s):  
Emmanouil Damilakis ◽  
Dimitrios Mavroudis ◽  
Maria Sfakianaki ◽  
John Souglakos
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Anticancer Agents ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Large Population ◽  
Tumor Infiltrating Lymphocytes ◽  
Imaging Biomarker ◽  
Tumor Mutational Burden

Immunotherapy has considerably increased the number of anticancer agents in many tumor types including metastatic colorectal cancer (mCRC). Anti-PD-1 (programmed death 1) and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) immune checkpoint inhibitors (ICI) have been shown to benefit the mCRC patients with mismatch repair deficiency (dMMR) or high microsatellite instability (MSI-H). However, ICI is not effective in mismatch repair proficient (pMMR) colorectal tumors, which constitute a large population of patients. Several clinical trials evaluating the efficacy of immunotherapy combined with chemotherapy, radiation therapy, or other agents are currently ongoing to extend the benefit of immunotherapy to pMMR mCRC cases. In dMMR patients, MSI testing through immunohistochemistry and/or polymerase chain reaction can be used to identify patients that will benefit from immunotherapy. Next-generation sequencing has the ability to detect MSI-H using a low amount of nucleic acids and its application in clinical practice is currently being explored. Preliminary data suggest that radiomics is capable of discriminating MSI from microsatellite stable mCRC and may play a role as an imaging biomarker in the future. Tumor mutational burden, neoantigen burden, tumor-infiltrating lymphocytes, immunoscore, and gastrointestinal microbiome are promising biomarkers that require further investigation and validation.

Association of KMT2C/D loss-of-function mutations with tumor infiltrating lymphocytes and response to immune checkpoint inhibitors in solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2587-2587
Author(s):  
Ruiqi Liu ◽  
Yanling Niu ◽  
Xin Zhang ◽  
Tonghui Ma
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Loss Of Function ◽  
Cancer Types ◽  
Immune Related Genes ◽  
Infiltrating Lymphocytes

2587 Background: Dysregulation of HMTs plays an important role in tumorigenesis. KMT2C and KMT2D are enzymatically active scaffold proteins that form the core of mammalian COMPASS complexes, which methylate the histone 3 lysine 4. Both KMT2C and KMT2D are involved in the regulation of gene expression. Therefore, we explored the associations of KMT2C/D loss-of-function (LOF) mutations with the expression of immune-related genes, the levels of tumor infiltrating lymphocytes (TILs), and response to immune checkpoint inhibitors (ICIs). Methods: KMT2C/D LOF mutations were defined as nonsense, frameshift, splice site variants within consensus regions, start lost, and stop lost/gained variants. An ICIs treatment cohort from the MSKCC was used for exploring the associations between KMT2C/D LOF mutations and ICIs efficacy. The RNA-Seq data obtained from the TCGA cohort was used for analysis of gene expression and the levels of TILs using CIBERSORT. Results: In MSKCC pan-cancer dataset, patients with KMT2C/D LOF mutations had a relatively longer median overall survival (OS) compared to those with non-LOF mutations, although the result did not reach statistical significance (P = 0.0832). Then we analyzed the predictive roles of KMT2C/D LOF mutations for each cancer type. The results showed that the predictive role of KMT2C/D LOF mutations for the clinical efficacy of ICIs therapy was only observed in colorectal cancer (P = 0.045). However, we did not find the associations of KMT2C/D LOF mutations with ICIs efficacy in bladder cancer, breast cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, NSCLC, and esophagogastric cancer. Consistently, analysis of TILs in colorectal cancer revealed that KMT2C/D LOF was associated with increased infiltration of several types of immune cells, such as CD8+ T cells (P = 0.0001), activated NK cells (P = 0.0001), M1 macrophage (P = 0.0005), M2 macrophage (P = 0.0115), and neutrophils (P = 0.0209). Meanwhile, regulatory T cells (Tregs) (P = 0.0048) and M0 macrophage (P = 0.0043) were dramatically decreased in KMT2C/D LOF group for colorectal cancer. Moreover, there were no significant relationships between KMT2C/D LOF and the levels of TILs in other cancer types. Our data also demonstrated that KMT2C and KMT2D could regulate the expression of more than 30 immune-related genes in colorectal cancer. Conclusions: Our data indicated that KMT2C/D LOF mutations were significantly correlated with better outcomes of ICIs therapy in colorectal cancer, suggesting it can be as a useful predictor for response to ICIs in colorectal cancer. Meanwhile, we found the associations of KMT2C/D LOF with the levels of TILs in colorectal cancer, but not in other cancer types, indicating that the efficacy of ICIs was consistent with the levels of TILs.

First Case Report of a Dramatic Radiographic Response to a Checkpoint Inhibitor in a Patient With Proficient Mismatch Repair Gene Expressing Metastatic Colorectal Cancer

2017 ◽  
pp. 1-4 ◽  
Author(s):  
Steven Sorscher ◽  
Jamie Resnick ◽  
Michael Goodman
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Response Rate ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
The United States ◽  
Mismatch Repair Gene ◽  
Repair Gene ◽  
First Case

Metastatic colorectal cancer (mCRC) remains the second most common cause of cancer death in the United States, and therapeutic options are limited. Recently, the checkpoint inhibitor pembrolizumab was given the Food and Drug Administration breakthrough therapy designation for the treatment of patients with mCRC whose tumors demonstrate deficient mismatch repair gene (dMMR) expression (as evidenced by microsatellite instability–high [MSI-H]). The designation was based on a phase II study showing that in patients with dMMR, an objective response rate of 40% was seen, whereas in patients with proficient mismatch repair gene mCRCs, the response rate was 0%. To our knowledge, this is the first case of a patient with a proficient mismatch repair gene mCRC whose tumor demonstrated a dramatic response to a checkpoint inhibitor. Because this patient’s tumor harbored amplification of both the PD-L1 and PD-L2 genes, the observed response was consistent with the presumed mechanism of action of checkpoint inhibitors. Checkpoint inhibitors are thought to activate a cytotoxic immune response that has been inhibited through tumor expression of PD-L1 and PD-L2. Given this result, dMMR in mCRC may not be the only predictor of responsiveness to checkpoint inhibition. As in non–small-cell lung cancer, PD-L1 or PD-L2 expression (or perhaps gene amplification) may also be predictors of checkpoint inhibitor efficacy.

scholarly journals Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2317 ◽  
Author(s):  
Federica Marmorino ◽  
Alessandra Boccaccino ◽  
Marco Maria Germani ◽  
Alfredo Falcone ◽  
Chiara Cremolini
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Dna Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Favorable Effect ◽  
Mutational Load ◽  
Dna Mismatch

The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.

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