title: IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs.
abstract: The presence of activated intratumoral T cells correlates clinically with better prognosis in patients with cancer. Although tumor vaccines can increase the number of tumor-specific CD8(+) T cells in systemic circulation, they frequently fail to increase the number of active and tumor reactive T cells within the tumor. Here we show that treatment with the pleiotropic cytokine interleukin-10 (IL-10) induces specific activation of tumor-resident CD8(+) T cells as well as their intratumoral expansion in several mouse tumor models. We found that inhibition of T-cell trafficking from lymphoid organs did not impair IL-10-induced tumor rejection or the activation of tumor-resident CD8(+) T cells. Tumor-resident CD8(+) T cells expressed elevated levels of the IL-10 receptor and were directly activated by IL-10, resulting in prominent phosphorylation of STAT3 and STAT1. Although CD4(+) T cells, regulatory T cells, NK cells, and dendritic cells have been reported as prominent targets of IL-10 in the tumor microenvironment, we found that expression of the IL-10R was required only on CD8(+) T cells to facilitate IL-10-induced tumor rejection as well as in situ expansion and proliferation of tumor-resident CD8 T cells. Together, our findings indicate that IL-10 activates CD8(+) T-cell-mediated tumor control and suggest that IL-10 may represent a potential tumor immunotherapy in human patients with cancer.
authors.affiliation: Merck Research Laboratories, Palo Alto, California, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Emmerich
authors.forename: John B
authors.initials: JB
authors.lastname: Mumm
authors.forename: Ivan H
authors.initials: IH
authors.lastname: Chan
authors.forename: Drake
authors.initials: D
authors.lastname: LaFace
authors.forename: Hoa
authors.initials: H
authors.lastname: Truong
authors.forename: Terrill
authors.initials: T
authors.lastname: McClanahan
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gorman
authors.forename: Martin
authors.initials: M
authors.lastname: Oft
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D008208:Lymphatic System / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D053701:Receptors, Interleukin-10; D016753:Interleukin-10