Oncoprotein signaling mediates tumor-specific inflammation and enhances tumor progression.
The RET/PTC3 (RP3) fusion protein is an oncogene expressed during the development of thyroid cancer and in thyroid epithelial cells of patients with Hashimoto's thyroiditis. RP3 has two immunological properties: 1) it encodes a chimeric protein including peptides that may be targets of antitumor immune responses and 2) it is a tyrosine kinase that can activate NF-kappaB transcriptional programs, induce secretion of proinflammatory mediators, and stimulate innate immunity. To distinguish the antigenic properties of the RP3 oncoprotein from its signaling function, a transplantable tumor system was developed. Tumors expressing the functional, but not mutant, form of RP3 show enhanced infiltration of CD8(+) lymphocytes, myeloid-derived CD11b(+)Gr1(+) cells, and enhanced growth in immunocompetent mice. In contrast, RP3 signaling mutant-expressing tumors maintained enhanced infiltration of CD8(+) lymphocytes did not enhance recruitment of CD11b(+)Gr1(+) cells and showed a decreased tumor incidence. These results implicate a role for RP3 function in enhancing a tumor-suppressive innate inflammatory response. These experiments support a mechanism whereby oncogenes can directly recruit and activate innate and adaptive immune cells, resulting in enhanced tumor progression.
Pufnock
Jeff S
JS
Department of Immunology/Microbiology and Otolaryngology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA 19107, USA.
Rothstein
Jay L
JL
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002291:Carcinoma, Papillary / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D016513:Mice, SCID; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology
D000951:Antigens, Neoplasm; D018836:Inflammation Mediators; D051096:Proto-Oncogene Proteins c-ret