TLR agonists: our best frenemy in cancer immunotherapy

Abstract

Various TLR agonists are currently under investigation in clinical trials for their ability to orchestrate antitumor immunity. The antitumor responses are largely attributed to their aptitude to stimulate APCs such as DCs which in turn, activate tumor-specific T cell responses. However, there is a potential for TLR signaling to occur on cells other than professional APCs that could negate antitumor responses or even worse, promote tumor growth. The impetus for this review is twofold. First, there is accumulating data demonstrating that the engagement of TLRs on different T cell subsets and different cancer types could promote tumor growth or conversely, contribute to antitumor responses. Second, the efficacy of TLR agonists as monotherapies to treat cancer patients has been limited. In this review, we discuss how TLR signaling within different T cell subsets and cancer cells can potentially impact the generation of antitumor responses. Based on evidence from preclinical models and clinical trials, we draw attention to several criteria that we believe must be considered when selecting TLR agonists for developing effective immunotherapeutic strategies against cancer.

Heterodimer‐specific TLR2 stimulation results in divergent functional outcomes in B‐cell precursor acute lymphoblastic leukemia

“…TLR2 ligation has been reported to induce either promising anti-cancer activity [39,[57][58][59][60] or confounding pro-tumorigenic effects [61][62][63][64][65]. Clearly, characterization of the precise function of each TLR in any given tumor type is critical [3], and the contrasting roles of TLR2 are thought to have significantly impaired the development of TLR2 agonists as adjuvants in anti-cancer immunotherapy [2,66]. Our results indicate that the specific heterodimerization partner can significantly impact the outcome of TLR2 ligation in human leukemia cells.…”

“…TLR-mediated effects are increasingly recognized as not only being species-, tissue-, and cell-specific, but also condition-and tumor dependent [3,11,[50][51][52][53][54][55]. This heterogeneity is evident from the contradictory findings from studies that investigated TLR2 signaling in various tumor models [3,11,53,56].…”

“…This heterogeneity is evident from the contradictory findings from studies that investigated TLR2 signaling in various tumor models [3,11,53,56]. TLR2 ligation has been reported to induce either promising anti-cancer activity [39,[57][58][59][60] or confounding pro-tumorigenic effects [61][62][63][64][65].…”

“…It is now widely accepted that tumor remissions induced by the proinflammatory activity of Coley's toxin, which contains various bacterial components, is mediated by the engagement of TollCorrespondence: Dr. Kirk R. Schultz e-mail: kschultz@mail.ubc.ca like receptors (TLRs) on immune cells [1][2][3][4][5]. TLRs are a family of germline-encoded pattern recognition receptors that induce innate and adaptive immune responses after binding pathogenand damage-associated molecular patterns [6][7][8][9][10].…”

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

“…Recently described examples are TRUCKs that co-express catalase to protect T cells from oxidative stress-mediated repression [30] and heparanase to improve T cell penetration through tumor stroma [31]. T cells engineered to secrete Toll-like receptor (TLR) ligands including TLR5 ligand can stimulate the TLR on T cells and on antigen-presenting cells which then activate a broad panel of tumorreactive T cells [32,33].…”