Clonotypic Diversification of Intratumoral T Cells Following Sipuleucel-T Treatment in Prostate Cancer Subjects.

Sipuleucel-T is an autologous cellular therapy for asymptomatic, or minimally symptomatic, metastatic castrate-resistant prostate cancer, designed to stimulate an immune response against prostate cancer. In a recent clinical trial (NCT00715104), we found that neoadjuvant sipuleucel-T increased the number of activated T cells within the tumor microenvironment. The current analysis examined whether sipuleucel-T altered adaptive T-cell responses by expanding pre-existing T cells or by recruiting new T cells to prostate tissue. Next-generation sequencing of the T-cell receptor (TCR) genes from blood or prostate tissue was used to quantitate and track T-cell clonotypes in these treated subjects with prostate cancer. At baseline, there was a significantly greater diversity of circulating TCR sequences in subjects with prostate cancer compared with healthy donors. Among healthy donors, circulating TCR sequence diversity remained unchanged over the same time interval. In contrast, sipuleucel-T treatment reduced circulating TCR sequence diversity versus baseline as measured by the Shannon index. Interestingly, sipuleucel-T treatment resulted in greater TCR sequence diversity in resected prostate tissue in sipuleucel-T-treated subjects versus tissue of nonsipuleucel-T-treated subjects with prostate cancer. Furthermore, sipuleucel-T increased TCR sequence commonality between blood and resected prostate tissue in treated versus untreated subjects with prostate cancer. The broadening of the TCR repertoire within the prostate tissue supports the hypothesis that sipuleucel-T treatment facilitates the recruitment of T cells into the prostate. Our results highlight the importance of assessing T-cell response to immunotherapy both in the periphery and in tumor tissue. Cancer Res; 76(13); 3711-8. ©2016 AACR.

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.