Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade

Clin Immunol. 2017 Oct:183:167-173. doi: 10.1016/j.clim.2017.09.002. Epub 2017 Sep 4.

Abstract

Persistent stimulation with antigens derived from viruses that establish chronic infections or tumour antigens results in the exhaustion of T cells. Coinhibitory receptors like PD-1 and CTLA-4 function as immune checkpoints on exhausted T cells. Blocking these molecules with antibodies improve immunity to cancer cells. Immune checkpoint inhibitors targeting other coinhibitory receptors might have a similar role in improving T cell function and thus also utility in cancer therapy. Using HIV-specific T cells as a model for exhaustion we have evaluated the capacity of antibodies targeting TIM-3, BTLA, CD160, LAG-3 and CTLA-4 alone or in combination with a PD-1 antibody to enhance proliferation and cytokine production in response to Gag and Nef peptides. Antibodies targeting BTLA and TIM-3 enhanced CD8 T cell proliferation. Moreover, our results indicate that blocking BTLA and TIM-3 in combination with PD-1 might be especially effective in enhancing responses of exhausted human T cells.

Keywords: BTLA; CD160; CTLA-4; Coinhibitory receptors; HIV-1; Immune checkpoints; LAG-3; PD-1; T cell exhaustion; TIM-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Blocking / pharmacology*
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antigens, CD / immunology
  • Antineoplastic Agents / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects
  • Cytokines / drug effects
  • Cytokines / immunology
  • Flow Cytometry
  • GPI-Linked Proteins / antagonists & inhibitors
  • GPI-Linked Proteins / immunology
  • HIV Antigens / immunology
  • HIV Infections / immunology
  • HIV Infections / virology
  • HIV-1 / immunology*
  • Hepatitis A Virus Cellular Receptor 2 / antagonists & inhibitors
  • Hepatitis A Virus Cellular Receptor 2 / immunology
  • Humans
  • Immunologic Factors / pharmacology*
  • Ipilimumab / pharmacology*
  • Lymphocyte Activation Gene 3 Protein
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / immunology
  • T-Lymphocytes / drug effects*

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal, Humanized
  • Antigens, CD
  • Antineoplastic Agents
  • BTLA protein, human
  • CD160 protein, human
  • Cytokines
  • GPI-Linked Proteins
  • HAVCR2 protein, human
  • HIV Antigens
  • Hepatitis A Virus Cellular Receptor 2
  • Immunologic Factors
  • Ipilimumab
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • pembrolizumab
  • Lymphocyte Activation Gene 3 Protein