scholarly journals Clinical outcomes of immune checkpoint blockades and the underlying immune escape mechanisms in squamous and adenocarcinoma NSCLC

2020 ◽  
Author(s):  
Yaru Tian ◽  
Xiaoyang Zhai ◽  
Weiwei Yan ◽  
Hui Zhu ◽  
Jinming Yu
Keyword(s):  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Immune Escape Mechanisms

scholarly journals The effects of PI3K/Akt/mTOR Signaling Pathway Inhibitors on Immune Evasion Mechanisms of Acute Myeloid Leukemia Cell Line

2021 ◽  
Author(s):  
Saeid Taghiloo ◽  
Saeid Norozi ◽  
Hossein Asgarian-Omran
Keyword(s):  
Cell Line ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Combined Treatment ◽  
Leukemia Cell ◽  
Leukemic Cells ◽  
Leukemia Cell Line ◽  
Akt Inhibitor ◽  
Immune Escape Mechanisms

Abstract Purpose: One of the most important immune escape mechanisms of AML is the up-regulation of immune checkpoint ligands. Herein, we have investigated the relationship between the inhibition of these pathways and the expression regulation of the immune checkpoint ligands in AML cells. Methods: HL-60 cell line was treated with different inhibitors including idelalisib as PI3K inhibitor, MK-2206 as Akt inhibitor, and everolimus as mTOR inhibitor either in single or combination therapy. Cell viability and apoptosis were evaluated using MTT and flow cytometry assays, respectively. The relative expression of PD-L1, galectin-9, and CD155 was determined by Real-Time PCR. Results: Our findings demonstrated decreasing in proliferation and increasing in apoptosis of HL60 cells after treatment with idelalisib, MK-2206, and everolimus. As expected, combined treatment showed more growth inhibition when compared to single treatment. Interestingly, our results demonstrated that the expression of PD-L1 and Gal-9 but not MK-2206, was decreased after treatment with idelalisib and everolimus. Regarding CD155, the expression of this molecule was downregulated after treatment with everolimus, but not idelalisib and MK-2206. However, combined treatment of HL-60 cells with two or three inhibitors decreased the expression levels of PD-L1, Gal-9 and CD155 checkpoint ligands. Conclusion: We showed that PI3K/Akt/mTOR pathway inhibitors not only serve as cytotoxic drugs, but also regulate the expression of immune checkpoint ligands and interfere with the immune evasion mechanisms of AML leukemic cells. Combinational therapy approaches to block these pathways might be a promising and novel therapeutic strategy for AML patients via interfering in immune escape mechanisms.

scholarly journals HLA dependent immune escape mechanisms in B-cell lymphomas: Implications for immune checkpoint inhibitor therapy?

2017 ◽  
Vol 6 (4) ◽  
pp. e1295202 ◽  
Author(s):  
Marcel Nijland ◽  
Rianne N. Veenstra ◽  
Lydia Visser ◽  
Chuanhui Xu ◽  
Kushi Kushekhar ◽  
...  
Keyword(s):  
B Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Immune Escape ◽  
Checkpoint Inhibitor ◽  
Inhibitor Therapy ◽  
B Cell Lymphomas ◽  
Checkpoint Inhibitor Therapy ◽  
Immune Escape Mechanisms

scholarly journals Immune Checkpoint Inhibition in Classical Hodgkin Lymphoma: From Early Achievements towards New Perspectives

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Diego De Goycoechea ◽  
Gregoire Stalder ◽  
Filipe Martins ◽  
Michel A. Duchosal
Keyword(s):  
Hodgkin Lymphoma ◽  
Immune Checkpoint ◽  
Immune Escape ◽  
Response Rates ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Classical Hodgkin Lymphoma ◽  
Immune Escape Mechanisms

Immune checkpoint inhibition (ICI) became one of the major breakthroughs in cancer treatment over the past decade and entered into therapy within standard oncohematology practice. ICI has demonstrated impressive response rates as salvage therapy in relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) and is now being tested as an adjunction to chemotherapy in the frontline settings. CHL exquisite sensitivity to PD-1/PD-L1 axis inhibition relies on a particular biological background. By contrast, non-Hodgkin lymphomas (NHL) have demonstrated heterogeneous response rates using ICI. These observations highlight discrepancies between various types of lymphomas in terms of genetic alterations, immune microenvironment interactions, and disease phenotype. This review aims to focus on cHL immune escape mechanisms, focusing on cHL biological sensitivity to PD-1 blockade. We will summarize the available data issued from clinical trials on ICI in cHL and its safety profile. Going beyond the current use of monoclonal antibodies (mAb) targeting immune checkpoints in clinical practice, we will offer an overview of new combinatory therapeutic perspectives where cHL immunotherapy may be considered.

scholarly journals Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

2021 ◽  
Vol 15 ◽  
pp. 117955492110355
Author(s):  
Tianhang Li ◽  
Tianyao Liu ◽  
Wenjie Zhu ◽  
Shangxun Xie ◽  
Zihan Zhao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Escape ◽  
Suppressor Cell ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Great Promise ◽  
Therapy Process ◽  
Myeloid Derived Suppressor Cell ◽  
Anti Cancer ◽  
Immune Suppressor

Immune-checkpoint blockade (ICB) demonstrated inspiring effect and great promise in anti-cancer therapy. However, many obstacles, such as drug resistance and difficulty in patient selection, limited the efficacy of ICB therapy and awaited to be overcome. By timely identification and intervention of the key immune-suppressive promotors in the tumor microenvironment (TME), we may better understand the mechanisms of cancer immune-escape and use novel strategies to enhance the therapeutic effect of ICB. Myeloid-derived suppressor cell (MDSC) is recognized as a major immune suppressor in the TME. In this review, we summarized the roles MDSC played in the cancer context, focusing on its negative biologic functions in ICB therapy, discussed the strategies targeted on MDSC to optimize the diagnosis and therapy process of ICB and improve the efficacy of ICB therapy against malignancies.

223 Racial differences in outcomes for metastatic renal cell carcinoma (mRCC) patients managed on immune-checkpoint inhibitor (ICI) therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A242-A242
Author(s):  
T Anders Olsen ◽  
Dylan Martini ◽  
Subir Goyal ◽  
Yuan Liu ◽  
Sean Evans ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
African American ◽  
Retrospective Study ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Clear Cell ◽  
Emory University ◽  
Caucasian Patients

BackgroundImmune checkpoint inhibitors (ICIs) have increased in prevalence for the treatment of metastatic clear-cell renal cell carcinoma (mccRCC) in recent years given their efficacy and favorable toxicity profile. However, there has been insufficient investigation in the literature of how clinical outcomes differ on the basis of race. In this paper, we investigated differences in clinical outcomes between African American (AA) and Caucasian mRCC patients treated with ICI therapy.MethodsWe performed a retrospective study of 198 patients with mRCC who received ICI at the Emory Winship Cancer Institute from 2015–2020. Clinical outcomes were measured by overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from ICI-initiation to date of death and radiographic or clinical progression, respectively. CB was defined as a best radiographic response of complete response, partial response, or stable disease maintained for at least 6 months per response evaluation criteria in solid tumors version 1.1. The association of self-identified race with OS and PFS was generally modeled by Cox proportional hazards model. Univariable and multivariable logistic regression models were used for binary outcomes of CB. The univariate association of immune-related adverse events (irAEs) and non-clear-cell RCC (nccRCC) with race was assessed using Chi-square test.ResultsOur cohort was made up of 38 AA (19%) and 160 Caucasian (81%) patients. Most of the patients were diagnosed with ccRCC (78%) and more than half received PD-1 monotherapy (57%). Most patients were international mRCC database consortium (IMDC) intermediate (57%) or poor-risk (25%) groups. AA patients displayed significantly shorter PFS (HR=1.52, 95% CI: 1.01–2.3, p=0.045) and trended towards decreased CB (OR=0.51, 95% CI: 0.22–1.17, p=0.111) in MVA (table 1). There was no difference in OS (HR=1.09, 95% CI: 0.61–1.95, p=0.778) between the two racial groups in MVA (table 1). On Kaplan-Meier method, AA patients had shorter median OS (17 vs 25 months, p=0.3676) and median PFS (3.1 vs 4.4 months, p=0.0676) relative to Caucasian patients (figure 1). Additionally, AA patients more commonly had nccRCC compared to Caucasian patients (41.7% vs 17.5% nccRCC, p-0.002). AA patients also trended towards a lower incidence of irAEs compared to Caucasian patients in UVA (23.7% vs 35.8%, p=0.153).Abstract 223 Table 1*MVA controlled for age, race, gender, IMDC risk group, number of prior lines of therapy, PD-1 monotherapy, and ccRCC**statistical significance at alpha < 0.05Abstract 223 Figure 1African-American (black) and Caucasian (white) for OS (left panel) and PFS (right panel)ConclusionsIn this group of mRCC patients treated with ICI, African American patients had significantly shorter PFS compared to Caucasian patients. These findings suggest race could play a role in the management of late-stage mRCC. Larger, prospective studies are needed to validate these findings.AcknowledgementsResearch reported in this publication was supported in part by the Breen Foundation and the Biostatistics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNot applicable.Ethics ApprovalThis retrospective study was approved by the Emory University Institutional Review Board.ConsentNot applicable.ReferencesNot applicable

Genetic ancestry and clinical outcomes to immune checkpoint inhibitors among seven common cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10536-10536
Author(s):  
Amin Nassar ◽  
Elio Adib ◽  
Sarah Abou Alaiwi ◽  
Elie Akl ◽  
Talal El Zarif ◽  
...  
Keyword(s):  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
East Asian ◽  
Genetic Ancestry ◽  
Sequencing Data ◽  
Histologic Subtype ◽  
Cancer Types

10536 Background: Prior studies and clinical trials report associations between self-reported race and clinical outcomes to Immune Checkpoint Inhibitors (ICIs). However, comprehensive studies of ancestry-associated differences in clinical outcomes have not been performed. We derived genetic ancestry scores and assessed clinical outcomes in 1341 patients with cancer treated with ICIs. Methods: Patients at the Dana-Farber Cancer Institute treated with ICIs only and with relevant cancer types and targeted exome sequencing data (Oncopanel) were included. Relevant cancer types included colorectal adenocarcinoma (CRC), esophagogastric adenocarcinoma (EGC), head and neck squamous cell carcinoma (HNSCC), melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma (UC). We developed a bioinformatics pipeline to infer fine-scale genetic ancestry for each patient (n=1341) directly from tumor sequencing data by leveraging off and on-target sequenced reads and external ancestry reference panels. Three ancestry scores were determined (African, East Asian, European). Overall survival (OS) and time-to-treatment failure (TTF) were compared by Cox logistic regression between ancestral populations. Hazard ratio (HR) was derived using multivariable analysis, adjusted for single versus combination therapy, prior lines of therapy, and tumor mutational burden (TMB, as percentiles). Results: Median follow-up was 37.8 months (m; interquartile range: 35.7-39.5m). Common cancer types included CRC (n=52), EGC (n=114), HNSCC (n=88), melanoma (n=274), NSCLC (n=571), RCC (n=99), and UC (n=143). A higher East Asian ancestry (EAS) was significantly associated with worse OS ( p=0.03) and TTF ( p=0.002) in patients with RCC, independent of the histologic subtype (Table). There was no significant association between any of the three ancestral populations and clinical outcomes in the other 6 cancer types. Conclusions: We described clinical outcomes to ICIs across three global populations in 7 cancers. As the medical field re-evaluates the use of self-reported race in clinical decision-making, we utilize a novel ancestry pipeline that can be readily applied to tumor-only sequencing panels and better characterize non-white populations. We find no ancestry differences in clinical outcomes except in patients with RCC treated with ICIs which will require future validation. We plan to analyze genomic correlates of response by ancestry in each of the cancer types to better understand these diverge clinical behaviors.[Table: see text]

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