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Oncoprotein Signaling Mediates Tumor-Specific Inflammation and Enhances Tumor Progression¹

Department of Immunology/Microbiology and Otolaryngology, Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, PA 19107

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-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Pennsylvania Tobacco Health Research Grant 4100026302 and by grants from the National Institutes of Health (CA76259 and AI063065 to J.L.R. and T32-CA09683 to J.L.P.).

² Current address: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98105.

³ Address correspondence to Dr. Jay L. Rothstein at the current address: Inflammation Research, Amgen, Inc., 1201 Amgen Court West, Seattle, WA 98119. E-mail address: jrothste{at}amgen.com

⁴ Abbreviations used in this paper: MDSC, myeloid-derived suppressor cell; PTC, papillary thyroid carcinoma; RP3, RET/PTC3; IRES, internal ribosome entry site; eGFP, enhanced GFP; MTS, (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethylphenyl)-2-(4-sulfophenyl)-2H-tetrazolium).