Insights into the Relationship between Toll Like Receptors and Gamma Delta T Cell Responses

Abstract

The tumor microenvironment is an important aspect of cancer biology that contributes to tumor initiation, tumor progression and responses to therapy. The composition and characteristics of the tumor microenvironment vary widely and are important in determining the anti-tumor immune response. Successful immunization requires activation of both innate and adaptive immunity. Generally, immune system is compromised in patients with cancer due to immune suppression, loss of tumor antigen expression and dysfunction of antigen presenting cells (APC). Thus, therapeutic immunization leading to cancer regression remains a significant challenge. Certain cells of the immune system, including dendritic cells (DCs) and gamma delta (γδ) T cells are capable of driving potent anti-tumor responses. The property of MHC-unrestricted cytotoxicity, high potential of cytokine release, tissue tropism and early activation in infections and malignant disease makes γδ T cells as an emerging candidate for immunotherapy. Various strategies are being developed to enhance anti-tumor immune responses of γδ T cells and DCs one of them is the use of novel adjuvants like toll like receptors (TLR) agonists, which enhance γδ T cell function directly or through DC activation, which has ability to prime γδ T cells. TLR agonists are being used clinically either alone or in combination with tumor antigens and has shown initial success in both enhancing immune responses and eliciting anti-tumor activity. TLR activated γδ T cells and DCs nurture each other's activation. This provides a potent base for first line of defense and manipulation of the adaptive response against pathogens and cancer. The available data provides a strong rationale for initiating combinatorial therapy for the treatment of diseases and this review will summarize the application of adjuvants (TLRs) for boosting immune response of γδ T cells to treat cancer and infectious diseases and their use in combinatorial therapy.

Keywords: dendritic cells; immunotherapy; toll like receptors; tumors; γδ T cells.

Figure 1

Improving γδ T cell functions by TLRs in combinatorial therapy. (A) TLR agonists induce effector function of γδ T cells through IFN-γ, TNF-α, IL-6 secretion, and increased expression of CD107a. (B) IFN-γ, TNF-α, and IL-6 secreted by γδ T cells and TLR agonists promote the maturation of dendritic cell. (C) γδ T cells upregulate CD86 and MHC I expression on DCs and are themselves activated through up-regulation of CD25, CD69, and cytokine production thereby modulating each other’s function. (D) Co-stimulation of γδ T cells with TLR agonists and IL-1β secreted by dendritic cells promote their polarization toward IL17 producing cells. (E) γδ TCR also recognizes the specific molecular patterns such as IPP, which are induced upon inhibition of mevalonate pathway by bisphosphonates. Moreover, NKG2D receptor on γδ T cells recognizes MICA/B or ULBP expressed on tumor cells. This binding enhances release of perforins and granzymes by the γδ T cells leading to tumor cell lysis. (F) TLR agonists act as adjuvants and can induce CD54 expression and downregulation of MHC class 1 on tumor cells. Interaction between CD54 and its ligand CD11a/CD18 trigger effector functions in γδ T cells. Downregulation of MHC class 1 molecule on tumor cells result in reduced signaling through the inhibitory receptor NKG2A on γδ T cells, which enhances the cytotoxic potential of γδ T cell.