scholarly journals The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses

2021 ◽  
Vol 11 ◽  
Author(s):  
Guanglin Cui
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Immune Cell ◽  
Basic Research ◽  
Final Analysis ◽  
Therapeutic Outcomes ◽  
Mutation Burden ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Cell Densities

Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more “sensitive” in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.

scholarly journals Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair–Deficient Cancer: Results From the Phase II KEYNOTE-158 Study

2020 ◽  
Vol 38 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Aurelien Marabelle ◽  
Dung T. Le ◽  
Paolo A. Ascierto ◽  
Anna Maria Di Giacomo ◽  
Ana De Jesus-Acosta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Previously Treated

PURPOSE Genomes of tumors that are deficient in DNA mismatch repair (dMMR) have high microsatellite instability (MSI-H) and harbor hundreds to thousands of somatic mutations that encode potential neoantigens. Such tumors are therefore likely to be immunogenic, triggering upregulation of immune checkpoint proteins. Pembrolizumab, an anti‒programmed death-1 monoclonal antibody, has antitumor activity against MSI-H/dMMR cancer. We report data from the phase II KEYNOTE-158 study of pembrolizumab in patients with previously treated, advanced noncolorectal MSI-H/dMMR cancer. PATIENTS AND METHODS Eligible patients with histologically/cytologically confirmed MSI-H/dMMR advanced noncolorectal cancer who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or patient withdrawal. Radiologic imaging was performed every 9 weeks for the first year of therapy and every 12 weeks thereafter. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by independent central radiologic review. RESULTS Among 233 enrolled patients, 27 tumor types were represented, with endometrial, gastric, cholangiocarcinoma, and pancreatic cancers being the most common. Median follow up was 13.4 months. Objective response rate was 34.3% (95% CI, 28.3% to 40.8%). Median progression-free survival was 4.1 months (95% CI, 2.4 to 4.9 months) and median overall survival was 23.5 months (95% CI, 13.5 months to not reached). Treatment-related adverse events occurred in 151 patients (64.8%). Thirty-four patients (14.6%) had grade 3 to 5 treatment-related adverse events. Grade 5 pneumonia occurred in one patient; there were no other treatment-related fatal adverse events. CONCLUSION Our study demonstrates the clinical benefit of anti–programmed death-1 therapy with pembrolizumab among patients with previously treated unresectable or metastatic MSI-H/dMMR noncolorectal cancer. Toxicity was consistent with previous experience of pembrolizumab monotherapy.

scholarly journals Identification of the pyroptosis‑related prognostic gene signature and the associated regulation axis in lung adenocarcinoma

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Wanli Lin ◽  
Ying Chen ◽  
Bomeng Wu ◽  
Ying chen ◽  
Zuwei Li
Keyword(s):  
Lung Adenocarcinoma ◽  
Microsatellite Instability ◽  
Bioinformatics Analysis ◽  
Immune Cell ◽  
Signalling Pathway ◽  
Functional Enrichment ◽  
Receptor Signalling ◽  
Cerna Network ◽  
Prognostic Gene ◽  
Mutation Burden

AbstractLung adenocarcinoma (LUAD) remains the most common deadly disease and has a poor prognosis. Pyroptosis could regulate tumour cell proliferation, invasion, and metastasis, thereby affecting the prognosis of cancer patients. However, the role of pyroptosis-related genes (PRGs) in LUAD remains unclear. In our study, comprehensive bioinformatics analysis was performed to construct a prognostic gene model and ceRNA network. The correlations between PRGs and tumour-immune infiltration, tumour mutation burden, and microsatellite instability were evaluated using Pearson’s correlation analysis. A total of 23 PRGs were upregulated or downregulated in LUAD. The genetic mutation variation landscape of PRG in LUAD was also summarised. Functional enrichment analysis revealed that these 33 PRGs were mainly involved in pyroptosis, the NOD-like receptor signalling pathway, and the Toll-like receptor signalling pathway. Prognosis analysis indicated a poor survival rate in LUAD patients with low expression of NLRP7, NLRP1, NLRP2, and NOD1 and high CASP6 expression. A prognostic PRG model constructed using the above five prognostic genes could predict the overall survival of LUAD patients with medium-to-high accuracy. Significant correlation was observed between prognostic PRGs and immune-cell infiltration, tumour mutation burden, and microsatellite instability. A ceRNA network was constructed to identify a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis in LUAD. In conclusion, we performed a comprehensive bioinformatics analysis and identified a prognostic PRG signature containing five genes (NLRP7, NLRP1, NLRP2, NOD1, and CASP6) for LUAD patients. Our results also identified a lncRNA KCNQ1OT1/miR-335-5p/NLRP1/NLRP7 regulatory axis, which may also play an important role in the progression of LUAD. Further study needs to be conducted to verify this result.

scholarly journals Recurrent Gallbladder Carcinoma With pMMR/MSS Achieved a Complete Response Following Camrelizumab Combined With Apatinib: A Case Report

2022 ◽  
Vol 11 ◽  
Author(s):  
Liting Zhong ◽  
Xiaoyu Liu ◽  
Zelei Li ◽  
Xuebing Zhang ◽  
Yuli Wang ◽  
...  
Keyword(s):  
Gallbladder Carcinoma ◽  
Complete Response ◽  
Limited Data ◽  
Effective Treatment Option ◽  
Tumor Mutation Burden ◽  
Angiogenic Therapy ◽  
Mutation Burden ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Durable Complete Response

Gallbladder carcinoma (GBC) with proficient mismatch repair (pMMR)/microsatellite stable (MSS) is associated with limited response to programmed death-1 (PD-1) inhibitor monotherapy. Limited data of PD-1 blockade combined with anti-angiogenic therapy in GBC are reported. One recurrent GBC patient with pMMR/MSS was treated with camrelizumab plus apatinib. After 4 cycles of combination therapy, the patient achieved a durable complete response with manageable toxicity. The next-generation sequencing and immunohistochemistry analysis showed that tumor mutation burden (TMB) was 7.26 mutants/Mb and PD-L1 expression was 10% (tumor proportion score) and 20% (immune proportion score). This case suggests that camrelizumab in combination with apatinib may be an effective treatment option for GBC patients with pMMR/MSS status, who have moderate expression of TMB and PD-L1. Additionally, TMB and PD-L1 expression may serve as potential biomarkers for predicting PD-1 inhibitor response of GBC. Furthermore, this needs to be verified in future studies.

Computational recognition of lncRNA signature of tumor-infiltrating B lymphocytes with potential implications in prognosis and immunotherapy of bladder cancer

2020 ◽  
Author(s):  
Meng Zhou ◽  
Zicheng Zhang ◽  
Siqi Bao ◽  
Ping Hou ◽  
Congcong Yan ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Noncoding Rna ◽  
Immune Cell ◽  
Functional Characterization ◽  
Predictive Biomarkers ◽  
Computational Framework ◽  
Gene Markers ◽  
Programmed Death ◽  
Clinical Covariates ◽  
Programmed Death 1

Abstract Long noncoding RNAs (lncRNAs) have been associated with cancer immunity regulation and the tumor microenvironment (TME). However, functions of lncRNAs of tumor-infiltrating B lymphocytes (TIL-Bs) and their clinical significance have not yet been fully elucidated. In the present study, a machine learning-based computational framework is presented for the identification of lncRNA signature of TIL-Bs (named ‘TILBlncSig’) through integrative analysis of immune, lncRNA and clinical profiles. The TILBlncSig comprising eight lncRNAs (TNRC6C-AS1, WASIR2, GUSBP11, OGFRP1, AC090515.2, PART1, MAFG-DT and LINC01184) was identified from the list of 141 B-cell-specific lncRNAs. The TILBlncSig was capable of distinguishing worse compared with improved survival outcomes across different independent patient datasets and was also independent of other clinical covariates. Functional characterization of TILBlncSig revealed it to be an indicator of infiltration of mononuclear immune cells (i.e. natural killer cells, B-cells and mast cells), and it was associated with hallmarks of cancer, as well as immunosuppressive phenotype. Furthermore, the TILBlncSig revealed predictive value for the survival outcome and immunotherapy response of patients with anti-programmed death-1 (PD-1) therapy and added significant predictive power to current immune checkpoint gene markers. The present study has highlighted the value of the TILBlncSig as an indicator of immune cell infiltration in the TME from a noncoding RNA perspective and strengthened the potential application of lncRNAs as predictive biomarkers of immunotherapy response, which warrants further investigation.

Programmed death-1 blockade in mismatch repair deficient colorectal cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. 103-103 ◽  
Author(s):  
Dung T. Le ◽  
Jennifer N. Uram ◽  
Hao Wang ◽  
Bjarne Bartlett ◽  
Holly Kemberling ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Programmed Death ◽  
Programmed Death 1

The Immunobiology of Kidney Cancer

2018 ◽  
Vol 36 (36) ◽  
pp. 3547-3552 ◽  
Author(s):  
Charles G. Drake ◽  
Mark N. Stein
Keyword(s):  
Kidney Cancer ◽  
Immune Checkpoint Blockade ◽  
Antiangiogenic Agents ◽  
Tumor Mutation Burden ◽  
Programmed Death Ligand 1 ◽  
T Cell Infiltration ◽  
Mutation Burden ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Tumor Types

Although kidney cancer (renal cell carcinoma [RCC]) is susceptible to immunotherapy, the immunologic aspects of the tumor microenvironment (TME) in RCC are relatively unique among tumor types. In RCC, baseline CD8 T-cell infiltration is associated with a worse prognosis. In addition, kidney cancer responds to programmed death-1/programmed death-ligand 1 blockade, despite a relatively low tumor mutation burden. Recent clinical data highlight the efficacy of combined immune checkpoint blockade and demonstrate that combining antiangiogenic agents with programmed death-1/programmed death-ligand 1 blockade has additive activity. Yet an important unanswered question in RCC is the nature of the antigens that are targeted by the immune system when immunotherapy is successful. Ongoing clinical studies are interrogating the multiple suppressive mechanisms in the RCC TME, including metabolic pathways such as those mediated by adenosine and tryptophan as well as cytokine-based therapies. Future regimens are likely to be combinatorial and may eventually be based on a broader understanding of the RCC TME and how it is modulated by both conventional and immune-based therapy.

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