Understanding genetic determinants of resistance to immune checkpoint blockers

2020 ◽  
Vol 65 ◽  
pp. 123-139 ◽  
Author(s):  
Sandrine Aspeslagh ◽  
Roman M. Chabanon ◽  
Stéphane Champiat ◽  
Sophie Postel-Vinay
Keyword(s):  
Immune Checkpoint ◽  
Genetic Determinants ◽  
Immune Checkpoint Blockers

scholarly journals Advances in the prediction of long-term effectiveness of immune checkpoint blockers for non-small-cell lung cancer

Immunotherapy ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 993-1003 ◽  
Author(s):  
Sara Elena Rebuzzi ◽  
Alessandro Leonetti ◽  
Marcello Tiseo ◽  
Francesco Facchinetti
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Small Cell ◽  
Small Cell Lung ◽  
Immune Checkpoint Blockers

561 ENHANCING RADIATION-INDUCED IMMUNOGENICITY IN THE MULTIMODAL TREATMENT OF ESOPHAGEAL CANCER: IS HYPOFRACTIONATION THE ANSWER?

2020 ◽  
Vol 33 (Supplement_1) ◽  
Author(s):  
N Donlon ◽  
M Davern ◽  
A Sheppard ◽  
J Elliott ◽  
N Ravi ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
T Lymphocytes ◽  
Cell Viability ◽  
Cancer Cell ◽  
Immune Checkpoint ◽  
Multimodal Treatment ◽  
Ex Vivo ◽  
Tumour Response ◽  
Immune Checkpoints ◽  
Immune Checkpoint Blockers

Abstract   Esophageal adenocarcinoma (EAC) is increasing exponentially year on year in Western civilisation, linked epidemiologically to GERD and obesity. It is characterized by a highly immunosuppressive tumour microenvironment (TME) and evasion of immune surveillance. A novel treatment option is upregulating immune mediated anti-tumour response via Immune Checkpoint Blockers (ICB). Methods The effects of immune checkpoint blockers were characterised in terms of proliferation, cytolysis and cancer cell viability. The basal expression of immune checkpoints (TIGIT, PD-1, PD-L1, PD-L2) and Damage Associated Molecular Patterns (Calreticulin, HMGB1) in EAC patients was profiled ex vivo using fresh tumor, blood and lymph-node tissue (n = 10) by flow cytometry. In an in-vitro study, T-lymphocytes were isolated and treated with Nivolumab, Pembrolizumab or Atezolizumab, activated and co-cultured for 48 hours with a panel of four esophageal cancer cell lines; OE33P, OE33R, FLO-1, FLO-1LM treated with 1.8Gy and 3.6Gy of radiation (Fig 1). Cytolysis was measured using a CCK8 assay.(n = 6). Results The expression of TIGIT, TIM-3, PD-1 and its ligands (PD-L1, PD-L2) were higher (p < 0.001) in EAC patients compared to age matched healthy controls. Similarly, when mimicking conditions of the TME including nutrient deprivation and hypoxia, this results in a significant (p < 0.001) increase in DAMP and ICB expression on CD3,4 and CD8 T cells in the TME when treated with radiation. T-lymphocytes induced by checkpoint blockers plus ionising radiation directly to the tumor resulted in the best repression of tumour growth with 3.6Gy inducing the highest rate of cytolysis (p < 0.001). ICB and radiation resulted in reduced cancer cell viability and proliferation. Conclusion Fractionated radiation can enhance immunologic function. In combination with ICB, this symbiotic relationship enhances the cytotoxic potential of T lymphocytes with conventional dosing, however, with hypofractionation, this signifies true immunogenicity, and as such this provides a basis for advocating for potential combination strategies with ICB in the multimodal treatment of EAC.

scholarly journals PT-112 induces immunogenic cell death and synergizes with immune checkpoint blockers in mouse tumor models

2020 ◽  
Vol 9 (1) ◽  
pp. 1721810 ◽  
Author(s):  
Takahiro Yamazaki ◽  
Aitziber Buqué ◽  
Tyler D. Ames ◽  
Lorenzo Galluzzi
Keyword(s):  
Cell Death ◽  
Immune Checkpoint ◽  
Immunogenic Cell Death ◽  
Mouse Tumor ◽  
Tumor Models ◽  
Immune Checkpoint Blockers ◽  
Mouse Tumor Models

scholarly journals Mesenchymal traits at the convergence of tumor-intrinsic and -extrinsic mechanisms of resistance to immune checkpoint blockers

2017 ◽  
Vol 1 (5) ◽  
pp. 471-486 ◽  
Author(s):  
Paola Trono ◽  
Antonella Sistigu ◽  
Belinda Palermo ◽  
Gennaro Ciliberto ◽  
Paola Nisticò
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Tumor Stroma ◽  
Gene Signature ◽  
Tumor Subtypes ◽  
Tumor Plasticity ◽  
Programmed Death ◽  
Immune Checkpoint Blockers

Targeting of immune checkpoint blockers (ICBs), such as cytotoxic T-lymphocyte antigen-4 and programmed-death 1/programmed-death ligand 1, has dramatically changed the landscape of cancer treatment. Seeing patients who were refractory to conventional therapy recover after immunotherapy, with high rates of objective durable responses and increased overall survival, has raised great enthusiasm in cancer care and research. However, to date, only a restricted portion of patients benefit from these therapies, due to natural and acquired resistance relying on the ever-evolving cross-talk between tumor and stromal cells. Here, we review the convergence of tumor-intrinsic and -extrinsic cues, both affecting tumor plasticity and tumor stroma leading to an immunosuppressive tumor microenvironment, which may account for the heterogeneous responses and resistance to ICB therapies. A deeper knowledge of the mechanisms and fingerprints involved in natural and acquired resistance is likely to bring clinical benefit to the majority of patients, offering important clues for overcoming drug resistance and boosting the effectiveness of treatment. We discuss the need to define tumor subtypes based on the tumor, immune and stromal gene signature and propose that the better we understand tumor mesenchymal traits, the more we will be able to identify predictive biomarkers of response to ICB treatments.

Research trends and public interests of immune checkpoint blockade in melanoma: a visualization and bibliometric analysis (Preprint)

2021 ◽  
Author(s):  
Yantao Xu ◽  
Zixi Jiang ◽  
Xinwei Kuang ◽  
Xiang Chen ◽  
Hong Liu
Keyword(s):  
Bibliometric Analysis ◽  
Immune Checkpoint ◽  
Data Extraction ◽  
The United States ◽  
Immune Checkpoint Blockade ◽  
Research Trends ◽  
Checkpoint Blockade ◽  
Public Interests ◽  
Immune Checkpoint Blockers ◽  
Authorship Analysis

BACKGROUND Melanoma is one of the most life-threatening skin cancers and immune checkpoint blockers (ICB) are widely used in the treatment of melanoma because of their remarkable efficacy. OBJECTIVE This study aimed to conduct a comprehensive bibliometric analysis of ICB in melanoma for the past decades, while exploring the research trends and public interests of immune checkpoint blockade in melanoma. METHODS We summarized the articles embodied in web of science core collection about immune checkpoint blockers in melanoma each year from 1950 to 2020. R package Bibliometrix was used to data extraction and the visualization of the distribution of publication years and top 10 core authors. The keywords citation burst analysis and co-citation network are performed by CiteSpace. Gunn map online world map was used to evaluate the distribution of countries and regions. Ranking was performed using the Standard Competition Ranking method. Except for these, the results of co-authorship analysis, co-occurrence are analyzed and visualized by VOSviewer. RESULTS After removing duplication, totally 9169 documents were included. Distribution of annual publications shows that the number of publications rose sharply from 2015 onwards, to a peak in 2020 or is yet to come. Spatial distribution indicated that there is a large gap between the amount of document published in other countries and the United States. The co-authorship analysis results clustered all 149 top published institution into 8 clusters, each approximately indicated one country, suggested that the international cooperation among various institutions should be strengthened, while the core author extraction indicate the publication peak change of authors. Keyword analysis unraveled the keywords clustering and top citation burst. Co-citation analysis of references analysis the reference from 2010 to 2020, unravel the citation number and centrality of top article. CONCLUSIONS This study revealed the trends in research interest and public interest of immune checkpoint blockade in melanoma, which may pave the way for further research.

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