A critical role for IL-12 in CCR5 induction on T cell receptor-triggered mouse CD4+ and CD8+ T cells

supporting

confidence: 66%

Definition of Key Variables for the Induction of Optimal NY-ESO-1–Specific T Cells in HLA Transgene Mice

Johannsen

Genolet

Legler

et al. 2010

“…CCR5 is expressed on the effector-effector/memory population (6,40,41) and this interaction is known to be critical for control of T cell responses in a number of models (4 -6, 31). Interestingly, the presence of IL-12 during T cell activation has been described to enhance the differentiation of T cells into a phenotype expressing CCR5 (42). The expression of IL-12 is closely tied to expression of IFN-␥ (43) and CCR5 is responsible for T cell migration to tumors in IL-12-treated mice (44).…”

Section: Discussionmentioning

confidence: 99%

Gene Therapy to Manipulate Effector T Cell Trafficking to Tumors for Immunotherapy

Gough¹,

Crittenden²,

Thanarajasingam³

et al. 2005

Strategies that generate tumor Ag-specific effector cells do not necessarily cure established tumors. We hypothesized that the relative efficiency with which tumor-specific effector cells reach the tumor is critical for therapy. We demonstrate in this study that activated T cells respond to the chemokine CCL3, both in vitro and in vivo, and we further demonstrate that expression of CCL3 within tumors increases the effector T cell infiltrate in those tumors. Importantly, we show that adenoviral gene transfer to cause expression of CCL3 within B16ova tumors in vivo increases the efficacy of adoptive transfer of tumor-specific effector OT1 T cells. We additionally demonstrate that such therapies result in endogenous immune responses to tumor Ags that are capable of protecting animals against subsequent tumor challenge. Strategies that modify the “visibility” of tumors have the potential to significantly enhance the efficacy of both vaccine and adoptive transfer therapies currently in development.

“…Priming of T cells in the lymph node is followed by migration to the periphery (25). To this end, TDLN CD8 ϩ T cells were also analyzed for the manifestation of a CD62L Ϫ CCR5 ϩ phenotype (26). The data shown in Fig.…”

Section: Intratumoral Il-12/gm-csf Induces the Activation And Prolifementioning

confidence: 99%

Central Role of Tumor-Associated CD8+ T Effector/Memory Cells in Restoring Systemic Antitumor Immunity

Kilinc

Harden

et al. 2009

Sustained delivery of IL-12 and GM-CSF to tumors induces the activation of tumor-resident CD8؉ T effector/memory cells (Tem) followed by cytotoxic CD8 ؉ T effector cell expansion. To determine whether the secondary effectors expanded from tumorassociated Tem or were primed de novo, activation kinetics of tumor-draining lymph node (TDLN) CD8 ؉ T cells were analyzed. Treatment promoted a 4-fold increase in the numbers of TDLN CD8؉ T cells displaying a CD69 ؉ CCR5 ؉ CD62L ؊ peripheryhoming effector phenotype by day 4 posttherapy. Pulse labeling of tumor and TDLN T cells with BrdU confirmed that proliferation occurred exclusively within the draining lymph nodes between days 1 and 4 with subsequent migration of primed CD8؉ T effectors to tumors on day 7. Day 4 CD8؉ T effector cells preferentially homed to and lysed experimental, but not control, tumors, establishing tumor specificity. To determine whether the secondary CD8 ؉ T effector cell response was dependent on activation of tumor-resident CD8 ؉ Tem, mice that were selectively depleted of tumor-infiltrating CD8 ؉ T cells were treated and monitored for T effector priming. In the absence of tumor-resident CD8 ؉ Tem, T effector cell expansion was completely abrogated in the TDLN, revealing that restoration of CD8 T he majority of tumor immunotherapy protocols are designed to induce antitumor T cell responses due to the exquisite specificity and potent cytotoxicity of T cells (1). However, such vaccines have generally been ineffective in achieving regression of established tumors in murine tumor models and in cancer patients (2). The observed lack of therapeutic efficacy is not simply due to the qualitative and/or quantitative inferiority of vaccine-induced antitumor T cells but rather appears to be associated with the immune-suppressive characteristics of the tumor microenvironment (3, 4); that is, even when potent and long-lasting tumor-specific T cell activity is generated, vaccine-induced cells are either unable to accumulate in tumors or are inactivated rapidly upon infiltration into tumor (3-6). Functional analyses of either vaccine-induced or natural tumor-infiltrating T cell populations have demonstrated that their quiescent phenotype is primarily associated with signaling defects (7,8). At the same time, others have shown that this phenotype is reversible and that purification and ex vivo culture of tumor-infiltrating T lymphocytes (TIL) 3 can result in the recovery of their cytotoxic function (9, 10). To this end, T cells expanded from tumors have been utilized in adoptive T cell transfer therapy to achieve durable clinical regressions in melanoma patients (11).Whether activation of TIL in situ can overcome tumor-mediated immune suppression and achieve tumor regression has been addressed in several studies. Targeting of inhibitory/regulatory mechanisms in tumors, including selective elimination of T suppressor cells or blocking of coinhibitory molecules can rescue concomitant immunity and lead to tumor regression even in the absence of additional immune st...