Combination of Immune Checkpoint Therapy with TLR Targeted Therapy

Toll-like receptors (TLRs) are the most important pattern-recognition receptors (PRRs) expressed by innate immune cells. They play a critical role in inducing antimicrobial innate and adaptive immune responses, such as tumor defense. Besides, TLR agonists are being combined with immune checkpoint blockade (ICB) or immunomodulatory agents to change the treatment paradigm in oncology.

Structure and Signaling Pathways of TLRs

TLRs are type I transmembrane glycoproteins that comprise one N-terminal extracellular domain (ECD) with a leucine-rich repetitive sequence, transmembrane domain (TM), and C-terminal cytoplasmic Toll/IL-1 receptor domain (TIR). TLRs are expressed in various immune cells, including monocytes, macrophages, and dendritic cells. TLRs have been found to play roles in DC maturation and antigen presentation leading to effective antitumor effects. Therefore, TLRs agonists are explored as anticancer agents or combined treatment to induce effective immune reactions against tumor antigens.
TLR signaling is a highly ordered biological process. Generally, ECD domain is responsible for binding pathogen-associated molecular patterns (PAMPs). Then, TIR domain recruits TIR-domain-containing adapter proteins, including myeloid differentiation primary response protein 88 (MyD88) and TIR-domain containing adaptor-inducing interferon-β (TRIF) that initiate signaling pathways to activate the NF-κB, interferon regulatory factor (IRFs), or MAPK to regulate the expression of IL-2, IL-6, IL-12, monocyte chemoattractant protein-1 (MCP-1), and TNF-α, etc. Ultimately, innate and adaptive immune responses are induced.

Fig.1 Toll-like receptors (TLRs) mediated signal transduction pathway. (Chen, 2020)

TLRs Agonists and Tumor Immunity

In a genetically engineered mouse melanoma model, Bald et al. used the prototypic immunostimulatory RNA polyinosinic: polycytidylic acid [poly (I: C)] to trigger the innate viral recognition receptors TLR3 and MDA5 and efficiently stimulate the type I IFN system. They revealed that TLR-3 activation could effectively induce type I interferon and synergize with anti-PD1 immune checkpoint blockade (ICB) therapy in melanoma. Besides, poly-ICLC has been used in combination with an anti-PD-L1 antibody for the treatment of colon cancer.
Houot et al. revealed that the combination of a TLR9 agonist and immunomodulatory T-cell antibodies (anti-OX40 and anti-CTLA-4) cured large and systemic lymphoma tumors without the need for chemotherapy and provided long-lasting immunity against tumor rechallenge in a lymphoma mouse model. Moreover, these reagents are becoming available for human clinical trials. Several ongoing clinical trials test the combination of TLR9 agonist with anti-PD1 therapy in various cancers.

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References

Chen, M.; et al. Targeting nuclear acid-mediated immunity in cancer immune checkpoint inhibitor therapies. Signal Transduction and Targeted Therapy. 2020, 5(1): 1-14.
Bald, T.; et al. Immune cell–poor melanomas benefit from PD-1 blockade after targeted type I IFN activation. Cancer discovery. 2014, 4(6): 674-687.
Houot, R.; Levy, R. T-cell modulation combined with intratumoral CpG cures lymphoma in a mouse model without the need for chemotherapy. Blood, The Journal of the American Society of Hematology. 2009, 113(15): 3546-3552.

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