BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer

Demerle, Clémence; Gorvel, Laurent; Olive, Daniel

doi:10.3389/fonc.2021.682007

Cited by 40 publications

(27 citation statements)

References 41 publications

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“…BTLA binds to herpes virus entry mediator ligand (HVEM) [ 54 ], which was not included in the current expression analysis. As BTLA expression is associated with T-cell exhaustion [ 21 ], the increased BTLA expression in OSCC tissue might indicate a state of T-cell exhaustion in OSCC.…”

Section: Discussionmentioning

confidence: 99%

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Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Weber

Lutz

Olmos

et al. 2022

Cancers

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Background: The involvement of immune cell infiltration and immune regulation in the progression of oral squamous cell carcinoma (OSCC) is shown. Anti-PD-1 therapy is approved for the treatment of advanced OSCC cases, but not all patients respond to immune checkpoint inhibitors. Hence, further targets for therapeutic approaches are needed. The number of identified cellular receptors with immune checkpoint function is constantly increasing. This study aimed to perform a comparative analysis of a large number of immune checkpoints in OSCC in order to identify possible targets for therapeutic application. Materials and Methods: A NanoString mRNA analysis was performed to assess the expression levels of 21 immune regulatory checkpoint molecules in OSCC tissue (n = 98) and healthy oral mucosa (NOM; n = 41). The expression rates were compared between the two groups, and their association with prognostic parameters was determined. Additionally, relevant correlations between the expression levels of different checkpoints were examined. Results: In OSCC tissue, significantly increased expression of CD115, CD163, CD68, CD86, CD96, GITRL, CD28 and PD-L1 was detected. Additionally, a marginally significant increase in CD8 expression was observed. BTLA and PD-1 levels were substantially increased, but the differential expression was not statistically significant. The expression of CD137L was significantly downregulated in OSCC compared to NOM. Correlations between immune checkpoint expression levels were demonstrated, and some occurred specifically in OSCC tissue. Conclusions: The upregulation of inhibitory receptors and ligands and the downregulation of activators could contribute to reduced effector T-cell function and could induce local immunosuppression in OSCC. Increased expression of activating actors of the immune system could be explained by the increased infiltration of myeloid cells and T-cells in OSCC tissue. The analysis contributes to the understanding of immune escape in OSCC and reveals potential targets for oral cancer immunotherapy.

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Section: Discussionmentioning

confidence: 99%

“…The B- and T-lymphocyte attenuator receptor (BTLA) is an inhibitory receptor of B- and T-cells. BTLA expression indicates terminally exhausted lymphocytes and was shown to be correlated with lung cancer progression [ 21 ]. CD137 is an activating checkpoint receptor of T-cells and NK cells but also of antigen-presenting cells [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Weber

Lutz

Olmos

et al. 2022

Cancers

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“…CD272 (BTLA, B and T lymphocyte attenuator) [ 276 ] was detected on T cell populations [ 277 , 278 , 279 , 280 , 281 ], as well as B cells and myeloid cell types [ 282 ]. Binding of CD272 to HVEM (herpes virus entry mediator) [ 283 ], which is widely expressed by leukocytes [ 284 , 285 , 286 , 287 , 288 , 289 ] and non-immune cell types like epithelial cells (EC) [ 287 ], was demonstrated to confer inhibition of B-cell [ 290 ] and T-cell [ 277 , 282 ] activation.…”

Section: Emerging Immune Checkpoints and Their Impact On Non-t-cell I...mentioning

confidence: 99%

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

Kuske

Haist

Jung

et al. 2022

Cancers

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The approval of immune checkpoint inhibitors (ICI) that serve to enhance effector T-cell anti-tumor responses has strongly improved success rates in the treatment of metastatic melanoma and other tumor types. The currently approved ICI constitute monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein (CTLA)-4 and anti-programmed cell death (PD)-1. By this, the T-cell-inhibitory CTLA-4/CD80/86 and PD-1/PD-1L/2L signaling axes are inhibited. This leads to sustained effector T-cell activity and circumvents the immune evasion of tumor cells, which frequently upregulate PD-L1 expression and modulate immune checkpoint molecule expression on leukocytes. As a result, profound clinical responses are observed in 40–60% of metastatic melanoma patients. Despite the pivotal role of T effector cells for triggering anti-tumor immunity, mounting evidence indicates that ICI efficacy may also be attributable to other cell types than T effector cells. In particular, emerging research has shown that ICI also impacts innate immune cells, such as myeloid cells, natural killer cells and innate lymphoid cells, which may amplify tumoricidal functions beyond triggering T effector cells, and thus improves clinical efficacy. Effects of ICI on non-T cells may additionally explain, in part, the character and extent of adverse effects associated with treatment. Deeper knowledge of these effects is required to further develop ICI treatment in terms of responsiveness of patients to treatment, to overcome resistance to ICI and to alleviate adverse effects. In this review we give an overview into the currently known immunomodulatory effects of ICI treatment in immune cell types other than the T cell compartment.

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“…The ligand for BTLA, herpes virus entry mediator was found to play an auxiliary role in immune escape in PD-L1-deficient lung tumors. 59 Transcriptome data from nasopharyngeal swabs (NPSs) and lung autopsy samples from COVID-19 cases have been published, demonstrating a pattern of upregulation of the mRNA levels of 8 ICs, including BTLA, LAG-3, CTLA-4 , and PDCD1 during acute COVID-19. 42 The above results are consistent with the findings that high concentrations of soluble BTLA can be detected in the plasma of critically ill COVID-19 patients.…”

Section: Btlamentioning

confidence: 99%

Immune checkpoint alterations and their blockade in COVID-19 patients

Tan

2022

Blood Science

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Coronavirus disease 2019 (COVID-19) is a highly contagious disease that seriously affects people’s lives. Immune dysfunction, which is characterized by abnormal expression of multiple immune checkpoint proteins (ICs) on immune cells, is associated with progression and poor prognosis for tumors and chronic infections. Immunotherapy targeting ICs has been well established in modulating immune function and improving clinical outcome for solid tumors and hematological malignancies. The role of ICs in different populations or COVID-19 stages and the impact of IC blockade remains unclear. In this review, we summarized current studies of alterations in ICs in COVID-19 to better understand immune changes and provide strategies for treating COVID-19 patients, particularly those with cancer.

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BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer

Cited by 40 publications

References 41 publications

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Beyond PD-L1—Identification of Further Potential Therapeutic Targets in Oral Cancer

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

Immune checkpoint alterations and their blockade in COVID-19 patients

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