Immune Checkpoint Inhibitor
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2021 ◽  
Vol 11 ◽  
Author(s):  
Zhenyu Yang ◽  
Yulan Deng ◽  
Jiahan Cheng ◽  
Shiyou Wei ◽  
Hao Luo ◽  
...  

BackgroundStratification of patients who could benefit from immune checkpoint inhibitor (ICI) therapy is of much importance. PD-1hiCD8+ T cells represent a newly identified and effective biomarker for ICI therapy response biomarker in lung cancer. Accurately quantifying these T cells using commonly available RNA sequencing (RNA-seq) data may extend their applications to more cancer types.MethodWe built a transcriptome signature of PD-1hiCD8+ T cells from bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data of tumor-infiltrating immune cells. The signature was validated by flow cytometry and in independent datasets. The clinical applications of the signature were explored in non-small-cell lung cancer, melanoma, gastric cancer, urothelial cancer, and a mouse model of breast cancer samples treated with ICI, and systematically evaluated across 21 cancer types in The Cancer Genome Atlas (TCGA). Its associations with other biomarkers were also determined.ResultsSignature scores could be used to identify the PD-1hiCD8+ T subset and were correlated with the fraction of PD-1hiCD8+ T cells in tumor tissue (Pearson correlation, R=0.76, p=0.0004). Furthermore, in the scRNA-seq dataset, we confirmed the capability of PD-1hiCD8+ T cells to secrete CXCL13, as well as their interactions with other immune cells. In 581 clinical samples and 204 mouse models treated with ICIs, high signature scores were associated with increased survival, and the signature achieved area under the receiver operating characteristic curve scores of 0.755 (ranging from 0.61 to 0.91) in predicting therapy response. In TCGA pan-cancer datasets, our signature scores were consistently correlated with therapy response (R=0.78, p<0.0001) and partially explained the diverse response rates among different cancer types. Finally, our signature generally outperformed other mRNA-based predictors and showed improved predictive performance when used in combination with tumor mutational burden (TMB). The signature score is available in the R package “PD1highCD8Tscore” (https://github.com/Liulab/PD1highCD8Tscore).ConclusionThrough estimating the fraction of the PD-1hiCD8+ T cell, our signature could predict response to ICI therapy across multiple cancers and could serve as a complementary biomarker to TMB.


2021 ◽  
Author(s):  
Wen Cheng

Abstract Urothelial bladder cancer (UBC) is one of the most lethal cancers worldwide, the 5-year survival rate remain poor with platinum-based chemotherapy regimens as the standard of cancer treatment protocol. Recent FDA approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in advanced UBC patients is changing the therapeutic landscape. Although the response to anti-PD-L1 is correlated to PD-L1 expression and tumor mutation burden, the molecule determinants of responsiveness or non-responsiveness to immune checkpoint inhibitor (ICI) is largely unknown. A published immunotherapy cohort with whole exome sequencing, RNAseq and clinic outcome data for 29 metastatic urothelial cancer patients was used, paralleled with The Cancer Genome Altas Bladder Cancer cohort for validation. Genomic mutational profiling, mutational signature, a panel genes in antigen presentation and interferon signaling in bladder cancer were delineated with little correlation with durable clinic benefit (DCB) or non-DCB of PD-L1 inhibitor treatment. Whereas, characterized immune-responsive or resistant associated genes showed differentially expressed between DCB group and non-DCB group. Further more, transcriptional signature and transcriptional regulators between DCB and non-DCB were identified from transcripome data. Our exploratory analyses provided multidimension view of complexity of determinants of immune-responsiveness and suggest the influences of transcriptional reprogram in immune checkpoint blockage therapy.


Author(s):  
Bernhard Scheiner ◽  
Matthias Pinter

SummaryWe present a case of a male patient with advanced hepatocellular carcinoma who developed hepatic and dermatological immune-related adverse events during treatment with the immune checkpoint inhibitor nivolumab. We discuss relevant aspects regarding the management of immune-related hepatic adverse events, including the incidence and onset of the event, the requirement for immune-modulating medication, resuming of immunotherapy, and the association between the occurrence of immune-related adverse events and the outcome.


Immunotherapy ◽  
2021 ◽  
Author(s):  
Pauline Rochefort ◽  
Françoise Desseigne ◽  
Valérie Bonadona ◽  
Sophie Dussart ◽  
Clélia Coutzac ◽  
...  

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base-excision repair, nucleotide-excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.


ESMO Open ◽  
2021 ◽  
Vol 6 (5) ◽  
pp. 100262
Author(s):  
A. Andrikopoulou ◽  
A.M. Korakiti ◽  
K. Apostolidou ◽  
M.A. Dimopoulos ◽  
F. Zagouri

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