Simultaneous targeting of toll- and nod-like receptors induces effective tumor-specific immune responses.
Toll-like receptor (TLR) ligands are increasingly being used as adjuvants in cancer vaccine trials to harness innate immunity and prime effective antitumor immune responses. Despite some success, enhancing tumor antigen presentation, promoting a protective antitumor response, and overcoming the immunosuppressive tumor microenvironment pose considerable challenges that necessitate further improvements in vaccine design. Here, we show that expression of the TLR ligand flagellin within tumor cells constitutes an effective antitumor vaccination strategy that relies on simultaneous engagement of TLR5 and the Nod-like receptors (NLRs) NLRC4/NAIP5 (neuronal apoptosis inhibitory protein 5) by flagellin along with associative recognition of tumor antigen for optimal antigen presentation to T cells. Although TLR5 signaling was critical for mediating rapid macrophage-dependent clearance of flagellin-expressing tumor cells in vivo, TLR5 and NLRC4/NAIP5 were equally important for priming antitumor CD4(+) and CD8(+) T cells and suppressing tumor growth. Vaccination with irradiated flagellin-expressing tumor cells prevented tumor development, and disrupting flagellin recognition by TLR5 or NLRC4/NAIP5 impaired protective immunization against an existing or subsequent tumor. Our findings delineate a new strategy to induce anticancer immune responses consisting of introducing microbial structures with dual TLR and NLR stimulatory activity into tumor cells. This ensures recognition of tumor-derived antigen within the inflammatory context of microbial recognition and additionally activates both the phagocytic and the cytosolic pathways of innate immune defense against the tumor.
Immunology Institute, Department of Medicine, The Tisch Cancer Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA.
Johan
J
Garaude
Andrew
A
Kent
Nico
N
van Rooijen
J Magarian
JM
Blander
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000276:immunology* / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000276:immunology* / Q000378:metabolism*; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D005408:Flagellin / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D051616:Neuronal Apoptosis-Inhibitory Protein / Q000276:immunology* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D019496:Cancer Vaccines; C512299:Ipaf protein, mouse; C496806:Naip5 protein, mouse; D051616:Neuronal Apoptosis-Inhibitory Protein; D051193:Toll-Like Receptors; D005408:Flagellin