Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter

Ritthipichai, Krit; Haymaker, Cara; Martinez, Melisa; Aschenbrenner, Andrew; Yi, Xiaohui; Zhang, Minying; Kale, Charuta; Vence, Luis M.; Roszik, Jason; Hailemichael, Yared; Overwijk, Willem W.; Varadarajan, Navin; Nurieva, Roza; Radvanyi, Laszlo G.; Hwu, Patrick; Bernatchez, Chantale

doi:10.1158/1078-0432.ccr-16-1217

Cited by 52 publications

(43 citation statements)

References 42 publications

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“…Depending on downstream signaling pathways, BTLA may transmit stimulatory or inhibitory signals possibly accounting for its controversial roles in malignant melanoma, gastric, and gall bladder cancer. [32][33][34][35][36][37] We show that BTLA was expressed on more than 50% of CD8 + T cells isolated from peripheral blood, tumor, and unaffected mucosa although expression was less on TILs compared to T UM . The functional and clinical significance of BTLA expression on TILs and T UM in rectal cancer has to be determined in future studies.…”

Section: Discussionmentioning

confidence: 78%

Localization-associated immune phenotypes of clonally expanded tumor-infiltrating T cells and distribution of their target antigens in rectal cancer

et al. 2019

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The degree and type of T cell infiltration influence rectal cancer prognosis regardless of classical tumor staging. We asked whether clonal expansion and tumor infiltration are restricted to selected-phenotype T cells; which clones are accessible in peripheral blood; and what the spatial distribution of their target antigens is. From five rectal cancer patients, we isolated paired tumor-infiltrating T cells (TILs) and T cells from unaffected rectum mucosa (T UM) using 13-parameter FACS single cell index sorting. TCRαβ sequences, cytokine, and transcription factor expression were determined with single cell sequencing. TILs and T UM occupied distinct phenotype compartments and clonal expansion predominantly occurred within CD8 + T cells. Expanded TIL clones identified by paired TCRαβ sequencing and exclusively detectable in the tumor showed characteristic PD-1 and TIM-3 expression. TCRβ repertoire sequencing identified 49 out of 149 expanded TIL clones circulating in peripheral blood and 41 (84%) of these were PD-1 − TIM-3 −. To determine whether clonal expansion of predominantly tumor-infiltrating T cell clones was driven by antigens uniquely presented in tumor tissue, selected TCRs were reconstructed and incubated with cells isolated from corresponding tumor or unaffected mucosa. The majority of clones exclusively detected in the tumor recognized antigen at both sites. In summary, rectal cancer is infiltrated with expanded distinct-phenotype T cell clones that either i) predominantly infiltrate the tumor, ii) predominantly infiltrate the unaffected mucosa, or iii) overlap between tumor, unaffected mucosa, and peripheral blood. However, the target antigens of predominantly tumorinfiltrating TIL clones do not appear to be restricted to tumor tissue.

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Section: Discussionmentioning

confidence: 78%

Localization-associated immune phenotypes of clonally expanded tumor-infiltrating T cells and distribution of their target antigens in rectal cancer

et al. 2019

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“…7 However, a recent publication suggests that BTLA can use the cytosolic adaptor GRB2 to trigger costimulatory signals in T cells. 8 Therefore, HVEM and BTLA appear to play a dual role in T cell activation depending on the ligands and intracytoplasmic effectors they interact with.…”

Section: Introductionmentioning

confidence: 99%

HVEM has a broader expression than PD-L1 and constitutes a negative prognostic marker and potential treatment target for melanoma

et al. 2019

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HVEM (Herpes Virus Entry Mediator) engagement of BTLA (B and T Lymphocyte Attenuator) triggers inhibitory signals in T cells and could play a role in evading antitumor immunity. Here, HVEM expression levels in melanoma metastases were analyzed by immunohistochemistry, correlated with overall survival (OS) in 116 patients, and validated by TCGA transcriptomic data. Coincident expression of HVEM and its ligand BTLA was studied in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry (n = 21) and immunofluorescence (n = 5). Candidate genes controlling HVEM expression in melanoma were defined by bioinformatics studies and validated by siRNA gene silencing. We found that in patients with AJCC stage III and IV melanoma, OS was poorer in those with high HVEM expression on melanoma cells, than in those with a low expression, by immunohistochemistry (p = .0160) or TCGA transcriptomics (p = .0282). We showed a coincident expression of HVEM at the surface of melanoma cells and of BTLA on TILs. HVEM was more widely expressed than PD-L1 in melanoma cells. From a mechanistic perspective, in contrast to PDL1, HVEM expression did not correlate with an IFNγ signature but with an aggressive gene signature. Interestingly, this signature contained MITF, a key player in melanoma biology, whose expression correlated strongly with HVEM. Finally, siRNA gene silencing validated MITF control of HVEM expression. In conclusion, HVEM expression seems to be a prognosis marker and targeting this axis by checkpoint-inhibitors may be of interest in metastatic melanoma.

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“…However, GRB2, which was suggested to bind BTLA (Gavrieli and Murphy, 2006;Ritthipichai et al, 2017), was not detected in this assay.…”

Section: Btla Recruits Both Shp1 and Shp2 While Pd-1 Recruits Only Shp2mentioning

confidence: 70%

BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling

Fulzele

Zhao

et al. 2019

Preprint

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T cell-mediated destruction of tumors and virus-infected cells is restricted by co-inhibitory receptors such as programmed cell death protein 1 (PD-1). Monoclonal antibodies blocking PD-1 have produced impressive clinical activity against human cancers, but durable response is limited to a minority of patients. Previous results suggest that B and T lymphocyte attenuator (BTLA), a co-inhibitory receptor structurally related to PD-1, may contribute to the resistance to PD-1 targeted therapy and co-blockade of BTLA can enhance the efficacy of anti-PD-1 immunotherapy. However, the biochemical mechanism by which BTLA represses T cell activity and to what extent the mechanism differs from that of PD-1 is unknown. Here we examine differences in the ability of BTLA and PD-1 to recruit effector molecules and regulate T cell signaling. We show that PD-1 and BTLA recruit different tyrosine phosphatases to regulate either CD28 or T cell antigen receptor (TCR)-signaling cascades. Our data reveal unexpected disparities between two structurally related immune checkpoints and two phosphatase paralogs.

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Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter

Cited by 52 publications

References 42 publications

Localization-associated immune phenotypes of clonally expanded tumor-infiltrating T cells and distribution of their target antigens in rectal cancer

Localization-associated immune phenotypes of clonally expanded tumor-infiltrating T cells and distribution of their target antigens in rectal cancer

HVEM has a broader expression than PD-L1 and constitutes a negative prognostic marker and potential treatment target for melanoma

BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling

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