Beyond the anti-PD-1/PD-L1 era: promising role of the BTLA/HVEM axis as a future target for cancer immunotherapy

Abstract

Recent introduction of monoclonal antibodies targeting immune checkpoints to harness antitumor immunity has revolutionized the cancer treatment landscape. The therapeutic success of immune checkpoint blockade (ICB)-based therapies mainly relies on PD-1/PD-L1 and CTLA-4 blockade. However, the limited overall responses and lack of reliable predictive biomarkers of patient´s response are major pitfalls limiting immunotherapy success. Hence, this reflects the compelling need of unveiling novel targets for immunotherapy that allow to expand the spectrum of ICB-based strategies to achieve optimal therapeutic efficacy and benefit for cancer patients. This review thoroughly dissects current molecular and functional knowledge of BTLA/HVEM axis and the future perspectives to become a target for cancer immunotherapy. BTLA/HVEM dysregulation is commonly found and linked to poor prognosis in solid and hematological malignancies. Moreover, circulating BTLA has been revealed as a blood-based predictive biomarker of immunotherapy response in various cancers. On this basis, BTLA/HVEM axis emerges as a novel promising target for cancer immunotherapy. This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

Pan-immune inflammation value as a prognostic biomarker for cancer patients treated with immune checkpoint inhibitors

“…Our analysis suggests that excluding any of the studies did not have a major impact on the OS HR. Specifically, the HR estimates for OS ranged from 1.810 (95% CI: 1.464-2.239) when excluding Zeng et al., 2021 ( 2 ) to 2.003 (95% CI: 1.585-2.531) when excluding Sooi et al., ( 18 ) ( Figure 5A ). In addition, the sensitivity analysis indicated that the removal of any one study did not have a major impact on the overall results of PFS.…”

“…Cancer, being the primary cause of mortality, constitutes a substantial menace to global public health as its burden continues to escalate ( 1 ). The recent emergence of monoclonal antibodies targeting immune checkpoints has fundamentally transformed the field of cancer therapy ( 2 , 3 ). The success of treatment based on immune checkpoint blockade (ICB) largely relies on blocking PD-1/PD-L1 and CTLA-4 ( 4 , 5 ).…”

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

“…HVEM is implicated in various immune regulatory processes, including promoting Treg differentiation, inhibiting antigen processing, and presenting major histocompatibility complexes I (MHC I) molecules and αβT. Furthermore, the expression of PD-1, CTLA-4, TIM-3, V-domain Ig suppressor of T cell activation (VISTA), and lymphocyte activating 3 (LAG3) positively correlates with HVEM, suggesting its potential role in immune suppression within the GBM microenvironment [ 94 , 95 ]. High levels of lysosomal-associated membrane protein 2A (LAMP2A) in GBM and the TME are associated with temozolomide (TMZ) resistance and tumor progression.…”

γδ T cells and the PD-1/PD-L1 axis: a love–hate relationship in the tumor microenvironment

“…Like PD-1, BTLA negatively regulates T cell activation. Despite both BTLA and PD-1 possessing ITSM and ITIM motifs, PD-1 predominantly relies on ITSM to achieve its inhibitory function, whereas BTLA necessitates the concurrent presence of both ITIM and ITSM [ 56 ]. Resting γδ T cells, especially naïve γδ T cells, express high levels of BTLA, which is downregulated in the T CM and T EM stages.…”