Table 1 Summary of studies on BTLA expression and function in cancer

Liao et al. [54]

PTCL

Chinese

RT-qPCR

↑ mRNA in T-cells;

↑ in patients with advanced disease

-

-

Carreras et al. [55]

FL

Western FL patients

IHC

Detected in the germinal center of the follicular area as well as in the interfollicular compartment;

In some cases, detected also in the mantle and marginal zone area

-

Yes; positive correlation

Quan et al. [56]

DLBCL

Chinese

FC

↑ % of BTLA + CD3 + T-cells;

↑ levels in patients with advanced disease

BTLA + CD8 + T-cells produced ↓ perforin and granzyme B;

BTLA + CD4+/CD8 + T-cells expressed ↑ levels of pSTAT3

-

Karabon et al. [25]

CLL

Polish

FC

↑ mRNA levels in B and T-cells;

↓ on CLL B-cells

BTLA + CD19 + and CD3 + less responsive to PMA stimulation

-

Sordo-Bahamonde et al. [57, 58]

CLL

Spanish

FC

↑ on CLL B-cells, T-cells, NK-cells

BTLA activation led to↓IL-2 and IFNγ production;

BTLA blockade resulted in ↑ IFNγ production and NK-cell/ CD8 + T-cell mediated response

Yes; positive correlation

Mittal et al. [59]

murine model of LC

-

FC

↑ on proportion of BTLA + CD8+/CD4 + T-cells

BTLA + CD8 + T-cells produced ↓ IL-2 and TNF

-

Wang et al. [60]

LC

Chinese

FC

↑ on pleural fluid T-cells in lung cancer patients

-

-

Thommen et al. [61]

NSCLC

Swiss

FC

Expressed on CD8 + TILs, but not on PB CD8 + T-cells

BTLA + CD8 + TIL co-expressed high levels of PD-1, TIM-3, CTLA-4, and LAG-3;

-

Li et al. [62]

NSCLC

Chinese

IHC

Expressed on tumor cells; ↑ in patients with lymph node metastasis and advanced disease

-

Yes; negative correlation

Shen et al. [63]

LUAD

Chinese

IHC

Expressed on TILs

-

-

Lou et al. [64]

LUAD

-

RS

↑ mRNA levels in patients with the present EMT

-

-

Zhang et al. [65]

LUAD

-

RS

↑ mRNA levels in low-risk group

-

-

Derré et al. [26]

melanoma

Swedes

FC

CD8 + T-cells expressed ↑ BTLA levels;

Differentiation of CD8 + T-cells into effector cells was associated with ↓ BTLA expression

-

-

Malissen et al. [66]

melanoma

French

FC, IHC

Expressed on CD4 + and CD8 + TILs in contiguity with HVEM + melanoma cells

-

-

Radvanyi et al. [67]

melanoma

American

FC

↑ frequencies of CD8 + BTLA + and CD8 + BTLA + TIM-3 + TILs in responders to ACT

-

-

Haymaker et al. [68]

melanoma

American

FC

↑ on CD8 + TILs in patients responding to ACT therapy

↓ CD8 + BTLA + TILs proliferation and cytokine production;

↑ CD8 + BTLA + TILs survival

-

Fourcade et al. [69]

melanoma

American

FC

↑ on tumor-specific NY-ESO-1 CD8 + T-cell

BTLA blockade ↑ IFN-γ, TNF, and IL-2 production and proliferation by tumor-specific NY-ESO-1 CD8 + IFNγ + T-cell

-

Gestermann et al. [70]

melanoma

-

-

Expressed on CD4 + and CD8 + TILs

BTLA blockade led to ↓ melanoma cell number and ↑ T-cell:melanoma cell ratio

-

Érsek et al. [71]

melanoma

Hungarians

FC

Under MAF stimulation, BTLA expression ↑ on CD45RO + non-naïve/memory cytotoxic T-cells

-

-

Dong et al. [72]

melanoma

-

RS

↑ mRNA and protein levels in patients with metastatic

-

Yes, positive correlation

Feng et al. [73]

GC

Chinese

IHC

Positive staining in gastric cancer cells

-

Yes, negative correlation

Lan et al. [74]

GC

Chinese

IHC

Positive staining mainly within the cytoplasm of gastric cancer cells;

↑ levels associated with lymph node metastasis

-

Yes, negative correlation

Azarafza et al. [75]

GC

Iranian

RT-qPCR

IHC

↑ mRNA and protein expression in advanced stages

-

-

Song et al. [76]

CRC

-

RS

↓ mRNA levels in cancer tissue;

↑ levels associated with lymph node metastasis;

Associated with the degree of tumor infiltration and expression of B, T, and NK-cells markers

Potential role in the regulation of TCR and BCR signaling pathways and NK-cell-mediated cytotoxicity pathways of TILs

Yes, positive correlation

Kamal et al. [78]

CRC

Egyptian

RT-qPCR

↑ mRNA in PBMCs;

↑ in advanced stages;

Correlation with CTLA-4, LAG-3, and TIM-3 levels

-

Yes; negative correlation

Sorrentino et al. [79]

CRC

-

RS

Correlation with FCRL4, SIGLEC6, and SIGLEC2 levels as well as with B and T-cell markers

-

Yes; negative correlation

Oguro et al. [80]

GBC

Japanese

IHC, IF

Expressed in the proportion of CD3+, CD4+, CD8+, and CD20 + TILs, CD14 + monocytes, CD68 + macrophages, CD1a+, CD207+, and CD208 + DCs

-

Yes; negative correlation

Zhao et al. [81]

HCC

Chinese

FC

↑ on CD4 + T-cells; ↑ % of PD-1 + BTLA + CD4 + TILs associated with advanced stages

↓ capacity for IFNγ production by BTLA + CD4 + T-cells

-

Liu et al. [82]

HCC

Chinese

FC

↑ on PB CD4 + T-cells

↓ capacity to IFNγ production;

BTLA blockade ↑ production of IFNγ in PB CD4 + and CD8 + T-cells

-

Yi et al. [83]

HCC

Chinese

IHC

↑ on CD8 + effector memory TILs

-

-

Yu et al. [84]

OSCC

-

RS

Positively correlated with PD-L1 expression;

Negatively correlated with the TMB

-

Yes; negative correlation

Weber at al [85].

OSCC

German

NS

↑ in tumor samples

-

-

Qian et al. [86]

TC

Chinese

FC

↑ on Tfh

-

-

Luo et al. [87]

TC

Chinese

IHC

Expressed on TILs

-

No correlation

Imai et al. [88]

EOC

Japanese

FC

Expressed on 37.6% of CD4 + TILs and 15.7% of CD8 + TILs;

Correlation between BTLA levels on CD4+/CD8 + TILs and age, stage, or histological type of EOC

-

-

Chen et al. [5]

EOC

Taiwan

RT-qPCR

Detected in 59% of patients;

BTLA + had ↑ incidences of advanced disease

-

Yes; negative correlation

Muenst et al. [89]

BC

Swiss

IHC, FC

Detected in 2.3% of cases

-

-

Fang et al. [90]

BC

-

RS

↓ mRNA expression

-

-

Filippi et al. [91]

BC

-

RS

↓ mRNA expression

-

Yes; negative correlation

Sekar et al. [92]

murine model of MC

-

FC, RS

Detected on type I NKT-cells

BTLA blockade led to ↓ tumor growth and to ↑ of NK1.1 + T-cells and PBS-57-loaded CD1d tetramer-recognizing type I NKT-cells numbers, and to ↑ production of perforin and granzyme B

No correlation

Woroniecka et al. [93]

GBM

Polish

FC

↓ on TILs

-

-

Shen et al. [94]

HGG

Chinese

FC

↑ on CD3 + CD4 + and CD3 + CD8-CD4- TILs;

↑ on PBMC

-

-

Choi et al. [97]

murine model of GBM

-

FC

↑ on TILs non-Treg CD4 + T-cells over time after tumor implantation

anti-PD-1 and anti-BTLA combination therapy resulted in ↑ IFN-γ expression and secretion by CD4 + and CD8 + TILs

-