Disulfide-Linked Peptides for Blocking BTLA/HVEM Binding.

Marta Spodzieja,Justyna Iwaszkiewicz,Sylwia Rodziewicz-Motowidło,Agnieszka Karczyńska,Valérie Cesson,Olivier Michielin,Adam Sieradzan,Katarzyna Węgrzyn,Igor Zhukov,Vincent Zoete,Katarzyna Kuncewicz,Martyna Maszota-Zieleniak,Laurent Derré,Daniel E Speiser

doi:10.3390/ijms21020636

Abstract

Immune checkpoints are crucial in the maintenance of antitumor immune responses. The activation or blockade of immune checkpoints is dependent on the interactions between receptors and ligands; such interactions can provide inhibitory or stimulatory signals, including the enhancement or suppression of T-cell proliferation, differentiation, and/or cytokine secretion. B-and T-lymphocyte attenuator (BTLA) is a lymphoid-specific cell surface receptor which is present on T-cells and interacts with herpes virus entry mediator (HVEM), which is present on tumor cells. The binding of HVEM to BTLA triggers an inhibitory signal which attenuates the immune response. This feature is interesting for studying the molecular interactions between HVEM and BTLA, as they may be targeted for novel immunotherapies. This work was based on the crystal structure of the BTLA/HVEM complex showing that BTLA binds the N-terminal cysteine-rich domain of HVEM. We investigated the amino acid sequence of HVEM and used molecular modeling methods to develop inhibitors of the BTLA/HVEM interaction. We synthesized novel compounds and determined their ability to interact with the BTLA protein and inhibit the formation of the BTLA/HVEM complex. Our results suggest that the HVEM (14–39) peptide is a potent inhibitor of the formation of the BTLA/HVEM protein complex.

Highlights

The recent development of immune checkpoint blockade therapies, which target regulatory pathways in T-cells to enhance antitumor immune responses, has led to important clinical advances and has provided a new weapon against cancer
Baatisoend: oGnluth6,isAinspfo7r,mGaluti8o,nG, tlhue14H,VPEroM17(,1T4–y3r92)3f,rGaglym3e0n, tGwlua3s1c,hLoesue3n2f,oTrhfur3r3th, eGrlsyt3u4d,iTeshra3s5a, pVoatle3n6t,iCalyisn3h7i,baitnodr oGfluB3T8L.AB/aHseVdEMoninthteisraicntfioornms.ation, the herpes virus entry mediator (HVEM) (14–39) fragment was chosen for further studies as a potential inhibitor of B-and T-lymphocyte attenuator (BTLA)/HVEM interactions
We focused on other inhibitory receptor–ligands: BTLA and HVEM

Summary

Introduction

The recent development of immune checkpoint blockade therapies, which target regulatory pathways in T-cells to enhance antitumor immune responses, has led to important clinical advances and has provided a new weapon against cancer. The currently applied immunotherapies are mainly focused on blocking programmed cell death 1/programmed cell death-ligand 1 (PD1/PD-L1) [1,2,3] and cytotoxic T-lymphocyte antigen-4/cluster of differentiation 80/86 (CTLA-4/CD80/CD86) [4,5] interactions, but other immune checkpoints and their ligands could be targeted. One of these is the B-and T-lymphocyte attenuator (BTLA) and its ligand, namely, the herpes virus entry mediator (HVEM). This has been suggested in different types of cancer, including gastric cancer [9], bladder cancer [10], hepatocellular carcinoma [11], and melanoma [12]

Methods

Results

Conclusion