Vidyarthi et al. demonstrated that stimulating human and murine protumorigenic M2 macrophages with a TLR3 ligand (TLR3L) converts them to a proinflammatory M1 phenotype, as indicated by the shift in the expression of costimulatory and inhibitory markers and cytokine production. Antibody blockade and genetic knockouts demonstrated the critical role for IFN-αβ signaling in repolarization. The converted macrophages exhibited enhanced antigen uptake and presentation, as well as increased capacity for T cell priming. In vivo, TLR3L treatment reduced tumor growth in mice with colon cancer.
During tumor progression, macrophages shift their protective M1-phenotype to pro-tumorigenic M2-subtype. Therefore, conversion of M2 to M1 phenotype may be a potential therapeutic intervention. TLRs are important pathogen recognition receptors expressed by cells of the immune system. Recently, a crucial role of TLR-3 has been suggested in cancer. Consequently, in the current study, we defined the role of TLR-3 in the reversion of M2-macrophages to M1. We analyzed the role of TLR-3 stimulation for skewing M2-macrophages to M1 at mRNA and protein level through qRT-PCR, flow cytometry, western blotting, and ELISA. The effectiveness of TLR-3L stimulation to revert M2-macrophages to M1 was evaluated in the murine tumor model. To determine the role of IFN-alphabeta signaling in vitro and in vivo, we used Ifnar1(-/-) macrophages and anti-IFN-alphabeta antibodies, respectively. We observed upregulation of M1-specific markers MHC-II and costimulatory molecules like CD86, CD80, and CD40 on M2-macrophages upon TLR-3 stimulation. In contrast, reduced expression of M2-indicators CD206, Tim-3, and pro-inflammatory cytokines was noticed. The administration of TLR-3L in the murine tumor reverted the M2-macrophages to M1-phenotype and regressed the tumor growth. The mechanism deciphered for macrophage reversion and controlling the tumor growth is dependent on IFN-alphabeta signaling pathway. The results indicate that the signaling through TLR-3 is important in protection against tumors by skewing M2-macrophages to protective M1-subtype.
Author Info: (1) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States. (
Author Info: (1) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States. (2) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. (3) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. (4) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. (5) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. (6) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. (7) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. (8) Department of Dermatology, Yale University School of Medicine, New Haven, CT, United States. (9) Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India. (10) Immunology Laboratory, CSIR-Institute of Microbial Technology, Chandigarh, India. Indian Institute of Technology, Ropar, India.
