Pan-cancer association of HLA gene expression with cancer prognosis and immunotherapy efficacy

Schaafsma, Evelien; Fugle, Chloe M.; Wang, Xiaofeng; Cheng, Chao

doi:10.1038/s41416-021-01400-2

Cited by 88 publications

(78 citation statements)

References 64 publications

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“…For instance, CD93 was recently found to improve tumor vascular functions to promote T-cell infiltration and antitumor immunity after blockade of its pathway ( Sun et al, 2021 ). In addition, we also found that CD93 expression was positively related to almost all immune-related genes, which are known to promote the growth of tumor cells and tumor angiogenesis as well as contribute to tumor metastasis ( Li et al, 2021 ; Schaafsma et al, 2021 ) in nearly all cancers, which further demonstrated the importance of CD93 in the process of immune regulation.…”

Section: Discussionsupporting

confidence: 51%

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis

Zhang

Zheng

Ding

et al. 2022

Front. Cell Dev. Biol.

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Background: The clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1, and PD-L1 has revolutionized the treatment of cancer. However, the majority of patients do not derive clinical benefit. Further development is needed to optimize the approach of ICI therapy. Immunotherapy combined with other forms of treatment is a rising strategy for boosting antitumor responses. CD93 was found to sensitize tumors to immune-checkpoint blocker therapy after the blockade of its pathway. However, its role in immune and ICB therapy across pan-cancer has remained unexplored.Methods: In this study, we provide a comprehensive investigation of CD93 expression in a pan-cancer manner involving 33 cancer types. We evaluated the association of CD93 expression with prognosis, mismatch repair, tumor mutation burden, and microsatellite instability, immune checkpoints, tumor microenvironment, and immune using multiple online datasets, including The Cancer Genome Atlas, Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, Tumor Immune Estimation Resource database, and Tumor Immune Single-cell Hub.Results: CD93 expression varied strongly among cancer types, and increased CD93 gene expression was associated with poor prognosis as well as higher immune factors in most cancer types. Additionally, the level of CD93 was significantly correlated with MMR, TMB, MSI, immune checkpoints, TME, and immune cell infiltration. Noticeably, our results mediated a strong positive contact between CD93 and CAFs, endothelial cells, myeloid dendritic cells, hematopoietic stem cells, mononuclear/macrophage subsets, and neutrophils while a negative correlation with Th1, MDSC, NK, and T-cell follicular helper in almost all cancers. Function analysis on CD93 revealed a link between itself and promoting cancers, inflammation, and angiogenesis.Conclusion: CD93 can function as a prognostic marker in various malignant tumors and is integral in TME and immune infiltration. Inhibition of the CD93 pathway may be a novel and promising strategy for immunotherapy in human cancer. Further explorations of the mechanisms of CD93 in the immune system may help improve cancer therapy methods.

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Section: Discussionsupporting

confidence: 51%

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis

Zhang

Zheng

Ding

et al. 2022

Front. Cell Dev. Biol.

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“…but which produce a spectrum of antigens that engage in a similar way the HLA system. Given that the success of immune blockade immunotherapy for cancer partly depends on the HLA genetic makeup of the patient 11 – 13 , the HLA-based cancer associations we report here could be useful in informing immunotherapy across various cancer types.…”

Section: Discussionmentioning

confidence: 95%

“…Specifically, Class I HLA molecules (HLA-A, -B, -C) present intracellular antigen peptides to CD8+ cytotoxic T cells to signal destruction of infected cells whereas HLA Class II molecules (HLA-DR, DQ, and DP genes) present endocytosed extracellular antigen peptides to CD4+ T cells to promote B-cell mediated antibody production and adaptive immunity. HLA has been increasingly implicated in various types of cancer 8 – 13 . Moreover, HLA has recently been implicated in the shared heritability across cancers with some loci evidencing unidirectional associations with cancer types and others demonstrating discordant associations with cancer types, highlighting varying associations between HLA and different types of cancer 8 .…”

Section: Introductionmentioning

confidence: 99%

Immunogenetic clustering of 30 cancers

James

Georgopoulos

2022

Sci Rep

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Human leukocyte antigen (HLA) genes have been implicated in cancer risk and shared heritability of different types of cancer. In this immunogenetic epidemiological study we first computed a Cancer-HLA profile for 30 cancer types characterized by the correlation between the prevalence of each cancer and the population frequency of 127 HLA alleles, and then used multidimensional scaling to evaluate the possible clustering of those Cancer-HLA associations. The results indicated the presence of three clusters, broadly reflecting digestive-skin-cervical cancers, reproductive and endocrine systems cancers, and brain and androgen-associated cancers. The clustering of cancer types documented here is discussed in terms of mechanisms underlying shared Cancer-HLA associations.

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“…However, Negrao et al reported no significant correlations between HLA-I zygosity and PFS or OS in NSCLC patients with ICI treatment [ 68 ]. Schaafsma et al analyzed 33 cancer types and reported that tumors with high HLA gene expression tended to have higher immune cell infiltration, including CD8 + T and NK cells, and a more immunologically active TME, thus leading to increased survival [ 69 ].…”

Section: Predictive Biomarkers Beyond Pd-l1 Expressionmentioning

confidence: 99%

Predictive Markers for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

Ushio

Murakami

Saito

2022

JCM

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Immune checkpoint inhibitors (ICIs) have dramatically improved the outcomes of non-small cell lung cancer patients and have increased the possibility of long-term survival. However, few patients benefit from ICIs, and no predictive biomarkers other than tumor programmed cell death ligand 1 (PD-L1) expression have been established. Hence, the identification of biomarkers is an urgent issue. This review outlines the current understanding of predictive markers for the efficacy of ICIs, including PD-L1, tumor mutation burden, DNA mismatch repair deficiency, microsatellite instability, CD8+ tumor-infiltrating lymphocytes, human leukocyte antigen class I, tumor/specific genotype, and blood biomarkers such as peripheral T-cell phenotype, neutrophil-to-lymphocyte ratio, interferon-gamma, and interleukin-8. A tremendous number of biomarkers are in development, but individual biomarkers are insufficient. Tissue biomarkers have issues in reproducibility and accuracy because of intratumoral heterogeneity and biopsy invasiveness. Furthermore, blood biomarkers have difficulty in reflecting the tumor microenvironment and therefore tend to be less predictive for the efficacy of ICIs than tissue samples. In addition to individual biomarkers, the development of composite markers, including novel technologies such as machine learning and high-throughput analysis, may make it easier to comprehensively analyze multiple biomarkers.

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Pan-cancer association of HLA gene expression with cancer prognosis and immunotherapy efficacy

Cited by 88 publications

References 64 publications

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis

CD93 Correlates With Immune Infiltration and Impacts Patient Immunotherapy Efficacy: A Pan-Cancer Analysis

Immunogenetic clustering of 30 cancers

Predictive Markers for Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer

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