Understanding how combinatorial targeting of TLRs and TNFR family costimulatory members promote enhanced T cell responses

ABSTRACT

Introduction: Due to the ability of pathogen-associated molecular patters and tumor necrosis factor receptor (TNFR) family costimulatory agonists to boost T cell responses, studies have combined Toll-like receptor (TLR) ligands with TNFR family costimulatory receptor agonists to induce impressive and long-lasting T cell responses. Although some studies have determined how these combinatorial vaccines promote enhanced T cell responses, much remains unknown about the mechanism used by these combinations to promote synergistic T cell responses – especially in settings of infectious diseases or cancer.

Areas covered: In this review, we look in detail at the signaling pathways induced by combinatorial targeting of TLR and TNFR family costimulatory members that help them promote synergistic T cell responses. Understanding this can greatly aid the development of novel vaccine regimens that promote cellular immune responses, which is essential for treating certain infectious diseases and cancer.

Expert opinion: Vaccines against some infectious diseases as well as therapeutic cancer vaccines require cellular immunity. Therefore, we evaluate here how signaling pathways induced by TLR ligand and costimulatory agonist combinations promote enhanced T cell responses during immunization with model antigens, viral pathogens, or tumor antigens. Once pathways that drive these combinatorial vaccines to boost T cell activation are identified, they can be incorporated in vaccines designed to target pathogens or cancer.

KEYWORDS:

• TLR adjuvants
• TNFR family costimulatory receptors
• T cell responses
• vaccines
• cancer
• signaling pathways
• infectious diseases
• tumor therapy

Article highlights

• Vaccines against some infectious diseases as well as cancer require a potent T cell response in addition to an antibody response.

• Combined administration of agonists to TLR and TNFR family costimulatory members results in synergistic or enhanced T cell responses.

• Understanding how signaling pathways induced by combined targeting of TLR/TNFR costimulatory family receptors promote enhanced T cell responses can aid in the design of novel vaccine combinations for certain infectious diseases and/or cancer.

• We summarize here how combined targeting of TLR/TNFR family costimulatory receptors induce different signaling pathways and/or molecules, which activate DCs, NK, and T cells that alone or together promote enhanced T cell responses and bridge the activation by TLR and TNFR family members with clonal expansion of T cells.

• Once known which pathways induced by these combinatorial treatments promote enhanced T cell responses, they can be targeted in vaccines or combined with other immune checkpoint inhibitors (PD-1 and CTLA-4) to increase the ratio of effector to regulatory T cells and further improve the efficacy of these vaccines.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

A Vella is the recipient of grant from the National Institutes of Health (RO1 AI042858).