Control of T-Cell–Mediated Immune Response by HLA Class I in Human Pancreatic Carcinoma

Ryschich, Eduard; Nötzel, Tanja; Hinz, Ulf; Autschbach, Frank; Ferguson, James; Şimon, Ioan; Weitz, Jürgen; Fröhlich, Boris; Klar, E.; Büchler, Markus W.; Schmidt, Jan

doi:10.1158/1078-0432.498.11.2

Cited by 176 publications

(19 citation statements)

References 26 publications

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Section: Discussionsupporting

confidence: 91%

“…Studies have reported the correlation between HLA-I deficiency and decreased tumor-infiltrating CD8-positive T lymphocytes in tumor nests in some types of cancers, such as lung and pancreatic cancer. [25][26][27] Our results of CD8 immunohistochemistry in gastric cancer was in line with these findings. These observations suggest that HLA-I deficiency benefits tumor cells by reducing antigen presentation to the immune system and subsequent evasion from T-cell infiltration.…”

Section: Discussionsupporting

confidence: 89%

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Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma

Iwasaki¹,

Shinozaki‐Ushiku²,

Kunita³

et al. 2021

American Journal of Surgical Pathology

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Immune checkpoint inhibitor therapy is effective only for a subset of patients with gastric cancer. Impaired neoantigen presentation caused by deficiency of human leukocyte antigen class I (HLA-I) has been reported as a common mechanism of immune evasion which is associated with resistance to immune checkpoint blockade. To elucidate the significance of HLA-I deficiency in gastric cancer with special focus on microsatellite instable (MSI) and Epstein-Barr virus (EBV)-positive tumors, we examined HLA-I expression on tumor cells and correlated the results with clinicopathologic features, programmed death-ligand 1 (PD-L1) expression, and degree of tumor-infiltrating immune cells. This study included 58 MSI, 44 EBV-positive, and 107 non-EBV non-MSI tumors for comparison. The frequency of HLA-I deficiency (≥1% tumor cells) was significantly higher in MSI tumors (52%) compared with EBV-positive tumors (23%) and the other tumors (28%). In contrast, PD-L1 expression levels were highest in EBV-positive tumors, followed by MSI tumors, with the lowest prevalence in the other tumors in both Tumor Proportion Score and Combined Positive Score. HLA-I deficiency was significantly more frequent in advanced tumors (pT2-4) than in early tumors (pT1) in MSI and non-EBV non-MSI subtypes. In addition, the degree of CD8-positive cells infiltration was significantly reduced in HLA-I deficient tumor areas compared with HLA-I preserved tumor area within a tumor. Based on our observations, HLA-I, as well as PD-L1, should be considered as a common mechanism of immune escape especially in the MSI subtype, and therefore could be a biomarker predicting response to immune checkpoint inhibitor therapy in gastric cancer.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 89%

Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma

Iwasaki¹,

Shinozaki‐Ushiku²,

Kunita³

et al. 2021

American Journal of Surgical Pathology

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“…Signals that stimulate CTLs for the tumor immune response mainly depend on the formation of the MHC‐I‐antigen peptide‐TCR complex, and defects or changes in MHC‐I molecules on the surface of tumor cells will lead to tumor cells to escape the immune attack by CTLs, thereby conferring a growth advantage to tumor cells. [ 19 ] Interestingly, our experiments showed that compared with M0‐Exos, M2‐Exos had no significant effect on the mRNA level or the mRNA stability of MHC‐I in glioma cells, but they did significantly reduce the MHC‐I protein level and protein stability ( Figure 4 a,b ; Figure S5a,b , Supporting Information). Therefore, we speculate that M2‐TAM‐derived exosomes promote tumor cells to evade CD8 + T‐cell‐mediated antitumor immune responses by promoting the degradation of the MHC‐I protein in glioma cells after translation.…”

Section: Resultsmentioning

confidence: 91%

Tumor‐Associated Macrophage‐Derived Exosomal LINC01232 Induces the Immune Escape in Glioma by Decreasing Surface MHC‐I Expression

Wang

Yang

et al. 2023

Advanced Science

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Tumor-associated macrophage (TAM) infiltration facilitates glioma malignancy, but the underlying mechanisms remain unclear. Herein, it is reported that TAMs secrete exosomal LINC01232 to induce tumor immune escape. Mechanistically, LINC01232 is found to directly bind E2F2 and promote E2F2 entry into the nucleus; the two synergistically promots the transcription of NBR1. The increase in binding between NBR1 binding and the ubiquitinating MHC-I protein through the ubiquitin domain causes an increase in the degradation of MHC-I in autophagolysosomes and a decrease in the expression of MHC-I on the surface of tumor cells, which in turn led to tumor cell escape from CD8 + CTL immune attack. Disruption of E2F2/NBR1/MHC-I signaling with shRNAs or blockade with the corresponding antibodies largely abolishes the tumor-supportive effects of LINC01232 and inhibits tumor growth driven by M2-type macrophages. Importantly, knockdown of LINC01232 enhances the expression of MHC-I on the surface of tumor cells and improves the response to reinfusion with CD8 + T cells. This study reveals the existence of critical molecular crosstalk between TAMs and glioma mediates through the LINC01232/E2F2/NBR1/MHC-I axis to support malignant tumor growth, indicating that targeting this axis may have therapeutic potential.

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“…Class I molecules present intracellular peptides to CD8+ T cells, while Class II molecules present extracellular peptides to CD4+ T cells. These distinct mechanisms enable the immune system to distinguish between different types of antigens 5,6 . Overall, the functioning of the HLA also known as major histocompatibility complex (MHC) system plays a critical role in immunity and is highly regulated and complex 7 …”

Section: Hla Immune Response and Susceptibility To Covid‐19mentioning

confidence: 99%

The role of HLA genetic variants in COVID‐19 susceptibility, severity, and mortality: A global review

Hoseinnezhad,

Soltani,

Ziarati

et al. 2024

Clinical Laboratory Analysis

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BackgroundThe COVID‐19 pandemic has had a profound global impact, with variations in susceptibility, severity, and mortality rates across different regions. While many factors can contribute to the spread and impact of the disease, specifically human leukocyte antigen (HLA) genetic variants have emerged as potential contributors to COVID‐19 outcomes.MethodsIn this comprehensive narrative review, we conducted a thorough literature search to identify relevant studies investigating the association between HLA genetic variants and COVID‐19 outcomes. Additionally, we analyzed allelic frequency data from diverse populations to assess differences in COVID‐19 incidence and severity.ResultsOur review provides insights into the immunological mechanisms involving HLA‐mediated responses to COVID‐19 and highlights potential research directions and therapeutic interventions. We found evidence suggesting that certain HLA alleles, such as HLA‐A02, may confer a lower risk of COVID‐19, while others, like HLA‐C04, may increase the risk of severe symptoms and mortality. Furthermore, our analysis of allele frequency distributions revealed significant variations among different populations.ConclusionConsidering host genetic variations, particularly HLA genetic variants, is crucial for understanding COVID‐19 susceptibility and severity. These findings have implications for personalized treatment and interventions based on an individual's genetic profile. However, further research is needed to unravel the precise mechanisms underlying the observed associations and explore the potential for targeted therapies or preventive measures based on HLA genetic variants.

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Control of T-Cell–Mediated Immune Response by HLA Class I in Human Pancreatic Carcinoma

Cited by 176 publications

References 26 publications

Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma

Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma

Tumor‐Associated Macrophage‐Derived Exosomal LINC01232 Induces the Immune Escape in Glioma by Decreasing Surface MHC‐I Expression

The role of HLA genetic variants in COVID‐19 susceptibility, severity, and mortality: A global review

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