Anti-HVEM mAb therapy improves antitumoral immunity both in vitro and in vivo, in a novel transgenic mouse model expressing human HVEM and BTLA molecules challenged with HVEM expressing tumors

Abstract

BackgroundTumor necrosis factor superfamily member 14 (TNFRSF14)/herpes virus entry mediator (HVEM) is the ligand for B and T lymphocyte attenuator (BTLA) and CD160-negative immune co-signaling molecules as well as viral proteins. Its expression is dysregulated with an overexpression in tumors and a connection with tumors of adverse prognosis.MethodsWe developed C57BL/6 mouse models co-expressing human (hu)BTLA and huHVEM as well as antagonistic monoclonal antibodies (mAbs) that completely prevent the interactions of HVEM with its ligands.ResultsHere, we show that the anti-HVEM18-10 mAb increases primary human αβ-T cells activity alone (CIS-activity) or in the presence of HVEM-expressing lung or colorectal cancer cells in vitro (TRANS-activity). Anti-HVEM18-10 synergizes with antiprogrammed death-ligand 1 (anti-PD-L1) mAb to activate T cells in the presence of PD-L1-positive tumors, but is sufficient to trigger T cell activation in the presence of PD-L1-negative cells. In order to better understand HVEM18-10 effects in vivo and especially disentangle its CIS and TRANS effects, we developed a knockin (KI) mouse model expressing human BTLA (huBTLA+/+) and a KI mouse model expressing both huBTLA+/+/huHVEM+/+(double KI (DKI)). In vivo preclinical experiments performed in both mouse models showed that HVEM18-10 treatment was efficient to decrease human HVEM+tumor growth. In the DKI model, anti-HVEM18-10 treatment induces a decrease of exhausted CD8+T cells and regulatory T cells and an increase of effector memory CD4+T cells within the tumor. Interestingly, mice which completely rejected tumors (±20%) did not develop tumors on rechallenge in both settings, therefore showing a marked T cell-memory phenotype effect.ConclusionsAltogether, our preclinical models validate anti-HVEM18-10 as a promising therapeutic antibody to use in clinics as a monotherapy or in combination with existing immunotherapies (antiprogrammed cell death protein 1/anti-PD-L1/anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4)).

Herpesvirus Entry Mediator as an Immune Checkpoint Target and a Potential Prognostic Biomarker in Myeloid and Lymphoid Leukemia

“…Accordingly, anti-HVEM mAbs enhanced γδ-T cell immune responses; however, this was against lymphoma [5,20]. Anti-HVEM 18-18 mAbs improved the activity of primary human αβ-T cells and decreased exhausted CD8 + and regulatory T cells [46]. In addition, administering an HVEM blockade in prostate tumor-bearing mice in vivo reduced tumor growth by twofold and reconstituted human T cells [21].…”

“…For the experimental design, as in previous studies, all experiments used a single variable and a control. Examples of the controls utilized in this study are Hek293 in vitro cells [4,[41][42][43], HVEM untreated tumor cells [46], unstained CD4 + T cells [30], and non-malignant healthy controls [35]. In addition, the replication of each experiment was conducted similarly to previous publications [30,35].…”

A Ferroptosis-Related lncRNAs Signature Predicts Prognosis of Colon Adenocarcinoma

“…Dysregulation of BTLA has been found in chronic lymphocytic leukemia, and the inhibition of BLTA in patients with chronic lymphocytic leukemia can effectively treat chronic lymphocytic leukemia. The knockout of human BTLA was found to reduce T cell-mediated antitumor response in a mouse model of COAD [33]. Leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) is highly expressed in tumor cells.…”

Modulation of blood T cell polyfunctionality and HVEM/BTLA expression are critical determinants of clinical outcome in anti-PD1-treated metastatic melanoma patients

“…This decrease could reflect a modulation in the state of differentiation of CD4+ and CD8+ T cells, as HVEM expression is downregulated during T cell differentiation. 42 However, no association between HVEM levels in T cells and the frequency of memory T cell subsets was observed (Supplementary Figure S8a). Alternatively, as a ligand for BTLA, 43 that belongs to the CD28 family and shares structural similarities with PD1 and CTLA-4 44 with an ITIM motif in its cytoplasmic tail, HVEM may be part of a resistance mechanism inhibiting both proliferation and cytokines production by T cells through cis-inhibition.…”

“… 41 Demerlé et al recently reported higher HVEM expression on less differentiated T cell subsets (naïve (T N ) and central memory (T CM )) compared to effector memory (T EM ), and early activated T cells. 42 The reduced proportion of T N and the absence of modulation of T CM subsets observed in MM patients compared to HD strongly argue in favor of an activated status of CD4+ and CD8+ T cells as illustrated by the high expression of PD1 and TIGIT.…”