BTLA blockade enhances Cancer therapy by inhibiting IL-6/IL-10-induced CD19high B lymphocytes

Chen, Yuli; Lin, Han‐Wei; Chien, Chung‐Liang; Lai, Yen-Ling; Sun, Wei‐Zen; Chen, Chi-An; Cheng, Wen‐Fang

doi:10.1186/s40425-019-0744-4

Cited by 70 publications

(67 citation statements)

References 52 publications

(76 reference statements)

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“…Studies established the singular role of BTLA as both co-stimulator and co-inhibitor to activated cancerous CD8 + T cells (Derre et al, 2010;Ritthipichai et al, 2017). The clinical trial in which the registration number was NCT00854399 revealed that BTLA detected in epithelial ovarian carcinoma (EOC) tissues can predict poor outcomes of patients, and chemotherapy combined with BTLA inhibitor can enhance immune activation and produces effective anti-tumor effects (Chen Y. L. et al, 2019). So far, it remains inconclusive about the mechanism of BTLA in CRC.…”

Section: Discussionmentioning

confidence: 99%

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Song

2020

Front. Mol. Biosci.

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Background: B and T lymphocyte attenuator (BTLA) is a co-signaling protein belonging to the CD28 immunoglobulin superfamily. However, the role of BTLA in prognosis and immunotherapy of colorectal cancer (CRC) remains unclear. Methods: We evaluated the expression of BTLA via the Oncomine and the cancer genome atlas (TCGA) database. We research the outcome among different BTLA expression patients by Kaplan-Meier curve. We used the Chi-Squared test and Cox regression analysis to identify potential risk factors. Besides, the correlations between BTLA and cancer immune infiltration were investigated via CIBERSORT. Results: Various cohorts showed that BTLA expression was lower in CRC compared to corresponding normal tissue. Moreover, low BTLA expression was correlated with poor overall survival in TCGA cohorts and Gene Expression Omnibus cohorts (GSE29623 and GSE17536). Low BTLA expression was associated with less lymph node metastasis (p = 0.0123). In the Cox proportional hazards model, BTLA was identified as a favorable prognostic factor. Naive B cells, memory B cells, CD8 T cells, CD4 memory resting T cells, follicular helper T (Tfh) cells, monocytes, resting natural killing (NK) cells, M0 macrophages, M1 macrophages, resting mast cells, and activated mast cells were affected by BTLA expression (all p < 0.01). Correlated immune markers and functional enrichment analysis revealed BTLA functioned in the T cell receptor signaling pathway, B cell receptor signaling pathway, and NK cell-mediated cytotoxicity pathway. Conclusion: These analyses suggest BTLA is a potential factor for extended survival and closely related to CD8 T cells, Tfh cells, B cells, and NK cells in CRC. We summarize these results that BTLA can be used as a prognostic biomarker and might contribute to developing novel CRC immunological treatment strategies.

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Section: Discussionmentioning

confidence: 99%

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Song

2020

Front. Mol. Biosci.

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“…BTLA is a negative regulator of BCR signaling that is downregulated after B cell activation [ 32 , 41 ]. Furthermore, BTLA + CD19 hi B cells were associated with poor outcome in ovarian cancer [ 42 ]. GITR expression in human B cells has not been reported before, but studies in mice revealed a weak expression, which was increased by activation of BCR and CD40 and suppressed by cytokines secreted from T cells [ 43 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Circulating Exosomes Inhibit B Cell Proliferation and Activity

Schroeder

Puntigam

Hofmann

et al. 2020

Cancers

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(1) Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a distinctive suppression of the anti-tumor immunity, both locally in the tumor microenvironment (TME) and the periphery. Tumor-derived exosomes mediate this immune suppression by directly suppressing T effector function and by inducing differentiation of regulatory T cells. However, little is known about the effects of exosomes on B cells. (2) Methods: Peripheral B cells from healthy donors and HNSCC patients were isolated and checkpoint receptor expression was analyzed by flow cytometry. Circulating exosomes were isolated from the plasma of HNSCC patients (n = 21) and healthy individuals (n = 10) by mini size-exclusion chromatography. B cells from healthy individuals were co-cultured with isolated exosomes for up to 4 days. Proliferation, viability, surface expression of checkpoint receptors, and intracellular signaling were analyzed in B cells by flow cytometry. (3) Results: Expression of the checkpoint receptors PD-1 and LAG3 was increased on B cells from HNSCC patients. The protein concentration of circulating exosomes was increased in HNSCC patients as compared to healthy donors. Both exosomes from healthy individuals and HNSCC patients inhibited B cell proliferation and survival, in vitro. Surface expression of inhibitory and stimulatory checkpoint receptors on B cells was modulated in co-culture with exosomes. In addition, an inhibitory effect of exosomes on B cell receptor (BCR) signaling was demonstrated in B cells. (4) Conclusions: Plasma-derived exosomes show inhibitory effects on the function of healthy B cells. Interestingly, these inhibitory effects are similar between exosomes from healthy individuals and HNSCC patients, suggesting a physiological B cell inhibitory role of circulating exosomes.

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“…On the other hand, the co-expression of MHC class II on tumor cells and LAG-3 on CD8 REP-TILs is a potential limitation for the anti-tumor reactivity of REP-TILs and suggests that the addition of an anti-LAG-3 blocking antibody might be beneficial in these patients. Similarly, the importance of BTLA in the microenvironment of ovarian cancer has recently been reported [36] and, though the immune regulatory pathway might be more complex, anti-BTLA therapy might also be beneficial in ACT [37]. Still, two patients showed no tumor expression of MHC class I or II which could limit the tumor recognition and T cell reactivity altogether.…”

Section: Discussionmentioning

confidence: 89%

Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer

et al. 2020

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Immune therapy is a promising field within oncology but has been unsuccessful in ovarian cancer (OC). Still, there is rationale and evidence supporting immune therapy in OC. We investigated the potential for adoptive cell therapy (ACT) from in vitro expanded tumor-infiltrating lymphocytes (TILs) in combination with checkpoint inhibitors (ICI) and conducted immunological testing of ex vivo expanded TILs (REP-TILs). Six patients with late-stage metastatic high-grade serous OC were treated with immune therapy consisting of ipilimumab followed by surgery to obtain TILs and infusion of REP-TILs, low-dose IL-2 and nivolumab. One patient achieved a partial response and 5 others experienced disease stabilization for up to 12 months. Analysis of the REP-TILs with flow-and masscytometry show primarily activated and differentiated effector memory T cells. REP-TILs showed in vitro reactivity and expression of inhibitory receptors, such as LAG-3 and PD-1. Furthermore, our data indicate that addition of ipilimumab therapy improves the T cell fold expansion during production, increase the level of CD8 T cell tumor reactivity, and favorably affect the T cell phenotype. We show that the combination of ICI and ACT is feasible and safe. With one partial response and one long-lasting SD, we demonstrated the potential of ACT in OC.

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BTLA blockade enhances Cancer therapy by inhibiting IL-6/IL-10-induced CD19high B lymphocytes

Cited by 70 publications

References 52 publications

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Friend or Foe: Prognostic and Immunotherapy Roles of BTLA in Colorectal Cancer

Circulating Exosomes Inhibit B Cell Proliferation and Activity

Adoptive cell therapy in combination with checkpoint inhibitors in ovarian cancer

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