PD-1 Blockade Promotes Emerging Checkpoint Inhibitors in Enhancing T Cell Responses to Allogeneic Dendritic Cells

Carmen Stecher,Christoph Höller,Claire Battin,Peter Steinberger,Katharina Grabmeier-Pfistershammer,Judith Leitner,Gerhard J Zlabinger,Markus Zettl

doi:10.3389/fimmu.2017.00572

Abstract

Immune checkpoint inhibitors, which target coinhibitory T cell molecules to promote anticancer immune responses, are on the rise to become a new pillar of cancer therapy. However, current immune checkpoint-based therapies are successful only in a subset of patients and acquired resistances pose additional challenges. Finding new targets and combining checkpoint inhibitors might help to overcome these limitations. In this study, human T cells stimulated with allogeneic dendritic cells (DCs) were used to compare immune checkpoint inhibitors targeting TIM-3, BTLA, LAG-3, CTLA-4, and TIGIT alone or in combination with a PD-1 antibody. We found that PD-1 blockade bears a unique potency to enhance T cell proliferation and cytokine production. Other checkpoint inhibitors failed to significantly augment T cell responses when used alone. However, antibodies to TIM-3, BTLA, LAG-3, and CTLA-4 enhanced T cell proliferation in presence of a PD-1 antibody. Upregulation of coinhibitory T cell receptors upon PD-1 blockade was identified as a potential mechanism for synergistic effects between checkpoint inhibitors. Donor-specific variation in response to immune checkpoint inhibitors was attributed to the T cells rather than DCs. Additionally, we analyzed the regulation of checkpoint molecules and their ligands on T cells and allogeneic DCs in coculture, which suggested a PD-1 blockade-dependent crosstalk between T cells and APC. Our results indicate that several immune checkpoint inhibitors have the capacity to enhance T cell responses when combined with PD-1 blockade. Additional in vitro studies on human T cells will be useful to identify antibody combinations with the potential to augment T cell responses in cancer patients.

Highlights

Researchers and clinicians have attempted to harness the immune system to fight and eradicate tumor cells for well over 100 years [1, 2]
We used cocultures of human CFSE-labeled T cells with allogeneic dendritic cells (DCs) to evaluate the capacity of immune checkpoint inhibitors targeting TIM-3, BTLA, CD160, TIGIT, LAG-3, and CTLA-4 alone or in combination with a PD-1 blocker to enhance human T cell responses
Antibodies to TIM-3 and LAG-3 augmented CD4 T cell proliferation, and the CTLA-4 antibody ipilimumab increased the proliferation in the CD8 subset when used in combination with PD-1 blockade

Summary

Introduction

Researchers and clinicians have attempted to harness the immune system to fight and eradicate tumor cells for well over 100 years [1, 2]. Broad clinical success has been achieved only recently with the advent of efficient blocking antibodies to T cell coinhibitory pathways–immune checkpoint inhibitors. The combined use of PD-1 and CTLA-4 antagonists appears to have enhanced clinical efficacy compared to monotherapy with PD-1 or CTLA-4 antibodies [11]. Several studies that have analyzed the function of blocking antibodies targeting novel immune checkpoints in human T cell responses in vitro have provided rationales for the therapeutic use of these checkpoint inhibitors [17,18,19,20,21]. Few studies have compared several different immune checkpoints and in addition there is limited information regarding synergies and redundancies in the use of PD-1 blockers and immune checkpoint inhibitors targeting other coinhibitory T cell pathways

Methods

Results

Conclusion