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

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.

Circulating exosomes from esophageal squamous cell carcinoma mediate the generation of B10 and PD‐1high Breg cells

“…Therapeutic Abs targeting PD‐1 on T cells have made great breakthroughs in clinical trials . In addition to T cells, PD‐1 was found on the surface of activated monocytes, natural killer cells, dendritic cells, and B cells . In hepatocellular carcinoma, PD‐1 hi Breg cells have been identified as a new B‐cell subset .…”

Anti-PD-1 Immunotherapy-Induced Flare of a Known Underlying Relapsing Vasculitis Mimicking Recurrent Cancer

“…Nevertheless, the severity of the GPA reactivation with only one dose suggests a limited therapeutic window for PD‐1 blockade in this patient. PD‐1 antagonism in healthy individuals upregulates other compensatory immune checkpoints ; the lack of change in other immune checkpoint receptors in our patient may reflect dysregulation of these other inhibitory pathways and suggests a central importance of the PD‐1 pathway in suppressing his GPA. Ultimately, a better understanding of the pathways that influence the immune microenvironment and response to immunotherapy may enable rational selection of therapies and minimize the risk of immune‐mediated toxicity in our patients.…”

Not All Immune Checkpoints Are Created Equal

“…Interestingly, HVEM-deficiency results in a similar phenotype, indicating that inhibitory BTLA signaling might play a dominant role in the HVEM network ( 48 ). Several reports have found that BTLA blockers can enhance human T cell responses when used alone or in combination with antibodies against PD-1 ( 49 – 52 ). Work by Derré and colleagues demonstrated that although BTLA is down-regulated during activation and differentiation, this receptor is prominently expressed on human T cells in the tumor microenvironment and can function to inhibit tumor-specific T cells ( 53 ).…”