Activated STAT5 Promotes Long-Lived Cytotoxic CD8+ T Cells That Induce Regression of Autochthonous Melanoma

Abstract

Immunotherapy based on adoptive transfer of tumor antigen-specific CD8 þ T cell (TC) is generally limited by poor in vivo expansion and tumor infiltration. In this study, we report that activated STAT5 transcription factors (STAT5CA) confer high efficiency on CD8 þ effector T cells (eTC) for host colonization after adoptive transfer. Engineered expression of STAT5CA in antigen-experienced TCs with poor replicative potential was also sufficient to convert them into long-lived antigen-responsive eTCs. In transplanted mastocytoma-or melanoma-bearing hosts, STAT5CA greatly enhanced the ability of eTCs to accumulate in tumors, become activated by tumor antigens, and to express the cytolytic factor granzyme B. Taken together, these properties contributed to an increase in tumor regression by STAT5CA-transduced, as compared with untransduced, TCs including when the latter control cells were combined with infusion of interleukin (IL)-2/anti-IL-2 complexes. In tumors arising in the autochthonous TiRP transgenic model of melanoma associated with systemic chronic inflammation, endogenous CD8 þ TCs were nonfunctional. In this setting, adoptive transfer of STAT5CA-transduced TCs produced superior antitumor effects compared with nontransduced TCs. Our findings imply that STAT5CA expression can render TCs resistant to the immunosuppressive environment of melanoma tumors, enhancing their ability to home to tumors and to maintain high granzyme B expression, as well as their capacity to stimulate granzyme B expression in endogenous TCs. Cancer Res; 72(1); 76-87. Ó2011 AACR.

Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells

“…We demonstrated that mbIL15-CAR T cells had submaximal pSTAT5 levels relative to control CAR T cells stimulated with exogenous IL-15 and that these cells attained a desired less differentiated phenotype. In other studies, T cells constitutively expressing activated STAT5 demonstrated enhanced persistence but not transformation (46), despite an activated effector phenotype (46,52). In summary, contrasting the previous studies (62,63,65,67), our assessments of AWD-mbIL15-CAR T cells did not demonstrate (i) log growth in vitro, (ii) uncontrolled expansion in vivo, (iii) aneuploidy, (iv) a homogeneous differentiated or activated population, or (v) clonal outgrowth, all of which predict favorable human application of mbIL15-CAR T cells.…”

IL-15 enhances the antitumor effect of human antigen-specific CD8+T cells by cellular senescence delay

“…Our results are consistent with recent studies where constitutively activated STAT5 signaling mediated strong antitumor effects and the inhibition of STAT3 led to an enhanced adoptive therapy effect. [70][71][72][73] The mechanisms revealed in this study provide the basis for future rational design of strategies to improve persistence of CD8 C T-cell therapy in the clinical setting.…”

The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells

“…4E). In this transplanted tumor model, tumor antigen-loss variants escape adoptive therapy by TCRP1A T cells leading to tumor regrowth after 20 d (17,24). Regression of the P511 tumor, which remained incomplete upon adoptive transfer of A20-transduced TCRP1A T cells, was also followed by a more robust tumor regrowth (Fig.…”

“…S1). Mice heterozygous for the H-2L d /P1A [35][36][37][38][39][40][41][42][43] -specific TCR-transgene (TCRP1A) (17) and luciferase expressing TCRP1A mice (TCRP1A-Luc) (24) were kept on the Rag-1 −/− B10.D2 background. P14 TCR mice (19), Rag-1 −/− B10.D2, and C57BL/6 (CD45.2) as well as congenic C57BL/6 (CD45.1) mice were also used.…”