Toll-like receptors in tumor immunotherapy

Abstract

Lymphodepletion with chemotherapeutic agents or total body irradiation (TBI) before adoptive transfer of tumor-specific T cells is a critical advancement in the treatment of patients with melanoma. More than 50% of patients that are refractory to other treatments experience an objective or curative response with this approach. Emerging data indicate that the key mechanisms underlying how TBI augments the functions of adoptively transferred T cells include (a) the depletion of regulatory T cells (T(reg)) and myeloid-derived suppressor cells that limit the function and proliferation of adoptively transferred cells; (b) the removal of immune cells that act as "sinks" for homeostatic cytokines, whose levels increase after lymphodepletion; and (c) the activation of the innate immune system via Toll-like receptor 4 signaling, which is engaged by microbial lipopolysaccharide that translocated across the radiation-injured gut. Here, we review these mechanisms and focus on the effect of Toll-like receptor agonists in adoptive immunotherapy. We also discuss alternate regimens to chemotherapy or TBI, which might be used to safely treat patients with advanced disease and promote tumor regression.

Fig. 1

Tumor destruction of metastatic disease in various anatomic sites by adoptively transferred tumor-specific T cells in the setting of lymphodepletion with chemotherapeutic agents and/or TBI. Computed tomography scan of tumors in patients with stage IV melanoma. A, multiple large metastatic liver lesions existed before the treatment (pretreatment) and then regressed dramatically after adoptive T-cell transfer (16+ mo). B, patients with brain and recurrent axillary metastases experience tumor regression. C, multiple large metastatic liver lesions existed before the treatment (pretreatment) and then regressed dramatically after adoptive T-cell transfer (18+ mo) in patients receiving chemotherapeutic reagents in conjunction with 200 cGy TBI plus HSC transplant. D, multiple large metastatic liver lesions existed before the treatment (pretreatment) and then regressed dramatically after adoptive T-cell transfer (8+ mo) in patients receiving chemotherapeutic reagents in conjunction with six fractionated doses of 200 cGy TBI (twice a week for 3 d; 12 Gy TBI total) plus HSC transplant.

Fig. 2

Tumor regression can be triggered by transgenic pmel-1Tcells. A, a mouse bearing a large, established, vascularized B16 mouse melanoma tumor shown after the start of treatment (19 d after tumor implantation). B, the same mouse (day 67).

Fig. 3

Adoptive cell therapy in a lymphoreplete host. A, in a lymphoreplete environment, antitumor responses induced by adoptively transferred T cells are impaired because of their reduced availability of homeostatic cytokines (including IL-2, IL-7, and IL-15) by immune cells that consume them (cytokine sinks, which might include B cells,Tcells, and natural killer cells); and the suppressive activities of T_reg cells, MDSCs, quiescent monocytes and dendritic cells (DC), and possibly natural killer cells. B, systemic chemotherapy or radiation before adoptive cell transfer alters the milieu of the tumor-bearing host. APCs are reduced in number by direct killing but there might be a net increase in lymphocyte activation because of reduced competition for antigen at the APC surfaces. At the same time, as a result of the translocation of microbial LPS after chemotherapeutic or radiation-induced injury to the gut, dendritic cells mature and migrate to the lymph node via TLR4 signaling. This TBI action increases the functionality of the adoptively transferred lymphocyte. Activating γ-chain cytokines, such as IL-2, IL-7, and IL-15, as well as inflammatory cytokines, such as IL-6, IL-12, and tumor necrosis factor-α, are increased because of the removal of cellular sinks, T_reg cells, MDSCs, and natural killer cells, and concomitant innate immune activation. Collectively, these modifications promote the full activation of adoptively transferred T cells and tumor destruction.

Fig. 4

LPS signals the TLR4 pathway on an APC (i.e., monocyte or dendritic cell). TLR4 is a pathogen-associated receptor for Gram-negative bacterial product LPS.TLR4 requires MD-2, a secreted molecule, to functionally interact with the LPS:LPS binding protein complex (LPB). CD14 stabilizes and enhances LPS signaling. TLR4 engagement of LPS leads to nuclear factor-κB translocation via MyD88-dependent and MyD88-independent pathway that involve the TIR domain–ontaining adapter protein TIRAP. Adapted by permission from MacMillan Publisher Ltd: Nature Immunology 4; 1144–1150; Copyright 2003.