Pattern recognition receptors of innate immunity and their application to tumor immunotherapy

Abstract

Dendritic cells (DC) begin maturation in response to complex stimuli consisting of antigens and pattern molecules (PAMP) for the activation of the immune system. Immune adjuvant usually contains PAMP. Infection represents one event that is capable of inducing such a complex set of stimuli. Recently, DC were subdivided into a number of subsets with distinct cell-surface markers, with each subset displaying unique differential maturation in response to pattern molecules to induce various types of effector cells. In the present study, we review how pattern recognition molecules and adaptors in each DC subset drive immune effector cells and their effect in the stimulated DC. Although tumor cells harbor tumor-associated antigens, they usually lack PAMP. Hence, we outline the properties of exogenously-added PAMP in the modulation of raising tumor immunity. In addition, we describe the mechanism by which DC-dependent natural killer activation is triggered for the induction of antitumor immunity.

Figure 1

MyD88 and Toll‐interleukin I receptor‐domain (TIR)‐containing adoptor molecule (TICAM‐1) pathways. MyD88 is an adaptor for all Toll‐like receptors (TLR), except TLR3 (a). TLR2 and TLR4 recruit MyD88 via the bridging adaptor Toll‐interleukin I receptor‐domain (TIR)‐containing adoptor protein (TIRAP) (MAL) (b). Other TLR directly recruit MyD88. MyD88 activates nuclear factor‐kappa β (NF‐κB) in most cell types, except plasmacytoid dendritic cells (pDC), which activate the interferan‐regulatory factor (IRF‐7) transcription factor. MyD88 pathway is involved in the production of pro‐inflammatory cytokines in most cells. In contrast, the MyD88 pathway in pDC and the TICAM‐1 pathway in myeloid dendritic cells (DC) activate the type interferon (IFN) promoter via IRF‐3 or IRF‐7 (b). TLR4 can recruit both MyD88 and TICAM‐1, whereas other TLR recruit either of them. Each TLR responds to different agonistic stimuli, as shown in Table 1. DC, dendritic cells; IFN, interferon; IRF, interferon‐regulatory factor; pDC, plasmacytoid DC; TICAM‐1, Toll‐interleukin 1 receptor domain (TIR)‐containing adaptor molecule; TIRAP, Toll‐interleukin 1 receptor (TIR) domain‐containing adapter protein; TLR, toll like receptor.

Figure 2

Selective induction of immune effector lymphocytes by different agonistic stimuli. Each pattern molecule (PAMP) has its own uniqueness in myeloid dendritic cell (mDC) maturation. Differential maturation of mDC results in different effector driving as shown. CD8 T, various CD4 T, and B cells are proliferated by myeloid DC (mDC) with different properties. Tumor regression is a marker for evaluating which lymphocytes are activated in response to pathogen‐associated molecular patterns (PAMP).

Figure 3

A molecular mechanism of myeloid dendritic cell (mDC)‐mediated natural killer (NK) activation. (a) CD11b+ bone marrow‐derived dendritic cells (BMDC) act for natural killer (NK) activation by double‐stranded (ds) RNA. NK cells express tumoricidal activity against major histocompatibility complex (MHC) low implant tumors if they are primed by polyI:C plus bone marrow‐derived dendritic cells (BMDC), but not other myeloid cells. Dendritic cell–NK cell–cell contact is essential for the induction of polyI:C‐mediated antitumor NK cells. (b) Route for mDC maturation for the induction of NK activation.^{( 39 )}

Figure 4

Diverged functions of myeloid cells in tumor mass. A variety of myeloid subsets reside in tumor masses. Some of the subsets exhibit an immune suppressive feature that facilitates escape of tumor cells from immune effectors. Since pattern molecules (PAMP) act on both myeloid dendritic cells (mDC) and myeloid‐derived immune suppressing cells, complicated immune responses occur in tumors. Selective maturation of mDC circumventing the exacerbation of tumor progression by myeloid suppressor cells should be considered as adjuvant therapy of cancer. DAMP, damage‐associated molecular patterns; MDSC, myeloid‐derived suppressor cells; PRR, pattern‐recognition receptors; TAM, tumor‐associated macrophages.