The landscape of novel and complementary targets for immunotherapy: an analysis of gene expression in the tumor microenvironment

Gaffney, Stephen G.; Perry, Elizabeth B.; Chen, Ping-Min; Greenstein, Andrew E.; Kaech, Susan M.; Townsend, Jeffrey P.

doi:10.18632/oncotarget.27027

Cited by 9 publications

(7 citation statements)

References 85 publications

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“…Despite the potential responses with long overall survival, but response rate still remains limited (less than 20%) (Franklin et al 2017 ). Several factors are closely related to the response of ICBs including immune phenotype, target gene expression and tumor mutation burden (Gaffney et al 2019 ; Gao et al 2016 ; Zaretsky et al 2016 ). Another important factor is loss of functions in the antigen processing and presentation, which governs generation, recognition, binding and presentation to the cell surface.…”

Section: Introductionmentioning

confidence: 99%

Insignificant effects of loss of heterozygosity in HLA in the efficacy of immune checkpoint blockade treatment

Yang

Kim

2022

Genes Genom

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Background It is assumed that loss of heterozygosity and allelic copy loss in HLA gene is associated with poor response rates in immune checkpoint inhibitor treatment. H-owever, the accurate extents or consistency in cancer types have not been explored. Objective The goal of this study is to investigate quantitative relationship between HLA allelic copy loss and response rates to immune checkpoint inhibitors. Also, tumor microenvironment was computationally assessed in the tumors with HLA copy loss to provide potential mechanisms for the relationships. Method A total of 282 whole exome sequencing data from three cohorts of patients who received immune checkpoint blockade immunotherapy were analyzed, including Anti-PDL1 treated in metastatic urothelial cancer (N = 216), anti-PD1 treated metastatic melanoma (N = 26), and anti-CTLA4 treated metastatic melanoma (N = 39). The LOHHLA algorithm was used to calculate allelic copy number loss at each HLA-A, -B, and -C locus, and further determine HLA allelic copy loss status. The HLA copy status and ICB response rates were analyzed for association using Fisher’s exact test. The CIBERSORT-absolute algorithm was then used to analyze the patient's immune environment, which represented loss of heterozygosity, using paired matched RNA sequencing data. Results Unlike the general expectation, HLA allelic copy loss was not significantly associated with the ICB responses. Moreover, the relationship showed a reversed relationship in HLA-A in the urothelial cancer (better ICB response in HLA copy loss). Regardless of the HLA copy status, the proportion of cytotoxic immune cells in the immune environment of patients was correlated with ICB response, which was higher in the loss of heterozygosity group in the urothelial cohort. Conclusion Although the loss of heterozygosity in HLA was generally expected to be an inhibitory factor in the immune treatment response by causing T cell immune evasion, our analysis demonstrates no explicit relationships.

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Section: Introductionmentioning

confidence: 99%

Insignificant effects of loss of heterozygosity in HLA in the efficacy of immune checkpoint blockade treatment

Yang

Kim

2022

Genes Genom

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“…Some patients with a high correlation of CD3E-PD-1 did not respond, while other patients with low correlation did respond to anti-PD-1 treatment. When examining anti-PD-1 responders and nonresponders in metastatic melanoma, scholars found a significantly higher correlation between CD3E and PD-1 between responders and nonresponders, which supports the tumor hypothesis related to CD3E expression in the microenvironment [28]. That can be used as a useful criterion for identifying new therapeutic targets with potential for therapeutic response.…”

Section: Discussionmentioning

confidence: 55%

PD‐1 Coexpression Gene Analysis and the Regulatory Network in Endometrial Cancer Based on Bioinformatics Analysis

Wang

Liu

Zhang

et al. 2021

BioMed Research International

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Gynecological malignancies are tumors of the female reproductive system, mainly cervical cancer, endometrial cancer, and ovarian cancer. Endometrial cancer (EC) is the most common gynecological malignant tumor in developed countries. The aim of this study was to construct a network of programmed cell death protein 1 (PD-1) coexpressed genes through bioinformatics analysis and screen the potential biomarkers of PD-1 in endometrial cancer. In addition, genes and pathways involved in PD-1 and modulating tumor immune status were identified. We select the EC transcriptomic dataset in TCGA to retrieve gene sets on the cBioPortal platform, and the PD-1 coexpressed genes were obtained on the platform. GO and KEGG enrichment analysis of coexpressed genes was performed using the DAVID database. The target protein-protein interaction (PPI) network was constructed using Cytoscape 3.7.1 software, and the hub genes were then screened. A total of 976 coexpression genes were obtained. The enrichment analysis showed that PD-1 coexpressed genes were significantly enriched in overall components of the cell structure, the interaction of cytokines with cytokine receptors, chemokine signaling pathways, and cell adhesion molecules (CAMs). Ten hub genes were obtained by node degree analysis. CD3E gene is involved in the prognosis and immune process of EC, and the expression level is related to PD-1 (Pearson correlation coefficient is 0.82, P < 0.01 ). Patients with low CD3E gene expression in EC have a poor prognosis. The coexpression hub genes of PD-1 are related to immunity, in which CD3E is a prognostic marker that is involved in the PD-1/PD-L1-induced tumor immune escape. This study provides a new area to study the mechanism of PD-1/PD-L1 in EC and the precise treatment with targeted drugs.

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“…Hart et al has reported that a reduced cell surface abundance of CD3E could lead to a significant inhibition of T cell killing capacity ( Hart et al, 2019 ). In contrast, the increased expression of CD3E was found markedly related to the effective response in 31 cancer types patients who received anti-PD1 immunotherapy ( Gaffney et al, 2019 ). CD3D has been reported as a potential biomarker for the response to ICIs and prognosis in cancers, including colon cancer and muscle-invasive bladder cancer ( Klintman et al, 2016 ; Shi et al, 2019 ; Yang et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma

Zuo

Xiong

Zeng

et al. 2021

Front. Mol. Biosci.

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Background: Cervical squamous cell carcinoma (CESC) is one of the most frequent malignancies in women worldwide. The level of immune cell infiltration and immune-related genes (IRGs) can significantly affect the prognosis and immunotherapy of CESC patients. Thus, this study aimed to identify an immune-related prognostic signature for CESC.Methods: TCGA-CESC cohorts, obtained from TCGA database, were divided into the training group and testing group; while GSE44001 dataset from GEO database was viewed as external validation group. ESTIMATE algorithm was applied to evaluate the infiltration levels of immune cells of CESC patients. IRGs were screened out through weighted gene co-expression network analysis (WGCNA). A multi-gene prognostic signature based on IRGs was constructed using LASSO penalized Cox proportional hazards regression, which was validated through Kaplan–Meier, Cox, and receiver operating characteristic curve (ROC) analyses. The abundance of immune cells was calculated using ssGSEA algorithm in the ImmuCellAI database, and the response to immunotherapy was evaluated using immunophenoscore (IPS) analysis and the TIDE algorithm.Results: In TCGA-CESC cohorts, higher levels of immune cell infiltration were closely associated with better prognoses. Moreover, a prognostic signature was constructed using three IRGs. Based on this given signature, Kaplan–Meier analysis suggested the significant differences in overall survival (OS) and the ROC analysis demonstrated its robust predictive potential for CESC prognosis, further confirmed by internal and external validation. Additionally, multivariate Cox analysis revealed that the three IRGs signature served as an independent prognostic factor for CESC. In the three-IRGs signature low-risk group, the infiltrating immune cells (B cells, CD4/8 + T cells, cytotoxic T cells, macrophages and so on) were much more abundant than that in high-risk group. Ultimately, IPS and TIDE analyses showed that low-risk CESC patients appeared to present with a better response to immunotherapy and a better prognosis than high-risk patients.Conclusion: The present prognostic signature based on three IRGs (CD3E, CD3D, LCK) was not only reliable for survival prediction but efficient to predict the clinical response to immunotherapy for CESC patients, which might assist in guiding more precise individual treatment in the future.

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The landscape of novel and complementary targets for immunotherapy: an analysis of gene expression in the tumor microenvironment

Cited by 9 publications

References 85 publications

Insignificant effects of loss of heterozygosity in HLA in the efficacy of immune checkpoint blockade treatment

Insignificant effects of loss of heterozygosity in HLA in the efficacy of immune checkpoint blockade treatment

PD‐1 Coexpression Gene Analysis and the Regulatory Network in Endometrial Cancer Based on Bioinformatics Analysis

Exploration of a Robust and Prognostic Immune Related Gene Signature for Cervical Squamous Cell Carcinoma

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