HLA class I antigen processing machinery defects in antitumor immunity and immunotherapy

Maggs, Luke; Sadagopan, Ananthan; Moghaddam, Ali Sanjari; Ferrone, Soldano

doi:10.1016/j.trecan.2021.07.006

Cited by 38 publications

(36 citation statements)

References 118 publications

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“…Besides, the expression of some human leukocyte antigens (HLAs) was lowly expressed in HS, which was also consistent with the results of fewer infiltration of pro-inflammation immune cells in HS ( Figure 7F ). A plenty of studies have confirmed that impediments to processing HLA would hinder the identification, migration, and infiltration ability of tumor-infiltrating lymphocytes (TILs), thus facilitating the proliferation and invasion of malignancy ( Dong et al, 2021 ; Maggs et al, 2021 ; Kawazu et al, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

Cao

Zhu

et al. 2022

Front. Genet.

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Hypoxia, a typical hallmark of numerous tumors, indicates poor infiltration of antitumor lymphocytes, as well as facilitates the development, progression, and drug resistance of malignant cells. Here, the present research was performed to identify novel hypoxia-related molecular markers and their correlation to the tumor immune microenvironment (TIME) in colon cancer. The expression of hypoxia-related gene signature was extracted from The Cancer Genome Atlas (TCGA) COAD cohort. Based on this signature, a risk score model was constructed using the Lasso regression model. Its discrimination ability and stability were validated in another independent cohort (GSE17536) from Gene Expression Omnibus (GEO) database. Moreover, molecular biology experiments (quantitative real-time PCR and multiple immunohistochemistry) were performed to validate the results of bioinformatics analyses. Three hub genes, including PPFIA4, SERPINE1, and STC2, were chosen to build the risk score model. All of these genes were increasingly expressed in the hypoxia subgroup (HS). Compared with the normoxia subgroup (NS), HS had worse pathological features (T, N, M, and stage) and overall survival (OS), more expression of immune checkpoint molecules, poorer infiltration of some pro-inflammation immune cells (CD4+ T cells and CD8+ T cells), and enriched infiltration of M0/M2 macrophages. After the risk model was proven to be valuable and stable, a nomogram was built based on this model and some clinicopathological factors. Moreover, it had been identified that three hub genes were all increasingly expressed in hypoxic conditions by quantitative real-time PCR (qPCR). The results of multiple immunohistochemistry (mIHC) also showed that higher expression of hub genes was associated with poorer infiltration of pro-inflammation immune cells (CD8+ T cells and M1 macrophages) and richer infiltration of anti-inflammation immune cells (Treg cells and M2 macrophages). In conclusion, the present study uncovered the relations among hypoxia, TIME, and clinicopathological features of colon cancer. It might provide new insight and a potential therapeutic target for immunotherapy.

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Section: Resultsmentioning

confidence: 99%

Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

Cao

Zhu

et al. 2022

Front. Genet.

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“…Indeed, loss of expression of HLA class I and APP components is one of the best-known mechanisms exploited by tumors to evade immune surveillance. The resulting reduced tumor antigen presentation has been associated with resistance to ICI therapy (20). However, there is a small percentage of patients in which ICI can still work despite of APP alterations, suggesting that, especially for tumors with high mutation burden, antigen presentation is not completely abolished and can represent an Achilles' heel of the tumour (80).…”

Section: Discussionmentioning

confidence: 99%

Targeting the antigen processing and presentation pathway to overcome resistance to immune checkpoint therapy

et al. 2022

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Despite the significant clinical advances with the use of immune checkpoint inhibitors (ICIs) in a wide range of cancer patients, response rates to the therapy are variable and do not always result in long-term tumor regression. The development of ICI-resistant disease is one of the pressing issue in clinical oncology, and the identification of new targets and combination therapies is a crucial point to improve response rates and duration. Antigen processing and presentation (APP) pathway is a key element for an efficient response to ICI therapy. Indeed, malignancies that do not express tumor antigens are typically poor infiltrated by T cells and unresponsive to ICIs. Therefore, improving tumor immunogenicity potentially increases the success rate of ICI therapy. In this review, we provide an overview of the key elements of the APP machinery that can be exploited to enhance tumor immunogenicity and increase the efficacy of ICI-based immunotherapy.

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“…Finally, it is the down-regulation of HLA-like neoantigen peptide genes that are common in cancer cells. Most HLA class I antigen-processing machinery defects ( >75%) are caused by epigenetic mechanisms or signal transduction disorders, so we can design reasonable strategies to correct them knowing that this change is non-structural ( Maggs et al, 2021 ). At present, for breast cancer with different characteristics, different types of immunotherapies have emerged, such as immune checkpoint inhibitors, mRNA vaccines, chimeric antigen receptor-modified T cells (CAR-T), and related nano-positioning technologies.…”

Section: Discussionmentioning

confidence: 99%

RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer

Shao

Wei

et al. 2022

Front. Genet.

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Purpose: This study aims to reveal the relationship between RNA N6-methyladenosine (m6A) regulators and tumor immune microenvironment (TME) in breast cancer, and to establish a risk model for predicting the occurrence and development of tumors.Patients and methods: In the present study, we respectively downloaded the transcriptome dataset of breast cancer from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database to analyze the mutation characteristics of m6A regulators and their expression profile in different clinicopathological groups. Then we used the weighted correlation network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO), and cox regression to construct a risk prediction model based on m6A-associated hub genes. In addition, Immune infiltration analysis and gene set enrichment analysis (GSEA) was used to evaluate the immune cell context and the enriched gene sets among the subgroups.Results: Compared with adjacent normal tissue, differentially expressed 24 m6A regulators were identified in breast cancer. According to the expression features of m6A regulators above, we established two subgroups of breast cancer, which were also surprisingly distinguished by the feature of the immune microenvironment. The Model based on modification patterns of m6A regulators could predict the patient’s T stage and evaluate their prognosis. Besides, the low m6aRiskscore group presents an immune-activated phenotype as well as a lower tumor mutation load, and its 5-years survival rate was 90.5%, while that of the high m6ariskscore group was only 74.1%. Finally, the cohort confirmed that age (p < 0.001) and m6aRiskscore (p < 0.001) are both risk factors for breast cancer in the multivariate regression.Conclusion: The m6A regulators play an important role in the regulation of breast tumor immune microenvironment and is helpful to provide guidance for clinical immunotherapy.

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HLA class I antigen processing machinery defects in antitumor immunity and immunotherapy

Cited by 38 publications

References 118 publications

Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

Novel Hypoxia-Associated Gene Signature Depicts Tumor Immune Microenvironment and Predicts Prognosis of Colon Cancer Patients

Targeting the antigen processing and presentation pathway to overcome resistance to immune checkpoint therapy

RNA N6-Methyladenosine Regulators Contribute to Tumor Immune Microenvironment and Have Clinical Prognostic Impact in Breast Cancer

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