Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells.
ABSTRACT Tumors often escape immune-mediated destruction by suppressing lymphocyte infiltration or effector function. New approaches are needed that overcome this suppression and thereby augment the tumoricidal capacity of tumor-reactive lymphocytes. The cytokine interleukin-15 (IL-15) promotes proliferation and effector capacity of CD8(+) T cells, natural killer (NK) cells, and NKT cells; however, it has a short half-life and high doses are needed to achieve functional responses in vivo. The biological activity of IL-15 can be dramatically increased by complexing this cytokine to its soluble receptor, IL-15R alpha. Here, we report that in vivo delivery of IL-15/IL-15R alpha complexes triggers rapid and significant regression of established solid tumors in two murine models. Despite a marked expansion of IL-2/IL-15R beta(+) cells in lymphoid organs and peripheral blood following treatment with IL-15/IL-15R alpha complexes, the destruction of solid tumors was orchestrated by tumor-resident rather than newly infiltrating CD8(+) T cells. Our data provide novel insights into the use of IL-15/IL-15R alpha complexes to relieve tumor-resident T cells from functional suppression by the tumor microenvironment and have significant implications for cancer immunotherapy and treatment of chronic infections.
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ABSTRACT: A major challenge of cancer immunotherapy is the persistence and outgrowth of subpopulations that lose expression of the target antigen. IL-15 is a potent cytokine that can promote organ-specific autoimmunity when up-regulated on tissue cells. Here we report that T cells eradicated 2-wk-old solid tumors that expressed IL-15, eliminating antigen-negative cells. In contrast, control tumors that lacked IL-15 expression consistently relapsed. Interestingly, even tumors lacking expression of cognate antigen were rejected when expressing IL-15, indicating that rejection after adoptive T-cell transfer was independent of cognate antigen expression. Nevertheless, the T-cell receptor of the transferred T cells influenced the outcome, consistent with the notion that T-cell receptor activation and effector status determine whether IL-15 can confer lymphokine killer activity-like properties to T cells. The effect was limited to the microenvironment of tumors expressing IL-15; there were no noticeable effects on contralateral tumors lacking IL-15. Taken together, these results indicate that expression of IL-15 in the tumor microenvironment may prevent the escape of antigen loss variants and subsequent tumor recurrence by enabling T cells to eliminate cancer cells lacking cognate antigen expression in a locally restricted manner.Proceedings of the National Academy of Sciences 05/2013; · 9.81 Impact Factor
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ABSTRACT: 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 tumor-associated 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(-) periphery-homing 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(+) Tem function was critical to the induction of secondary T effectors. T cell priming failed to occur in IFN-gamma or perforin knockout mice, demonstrating that the requirement for Tem activation was associated with induction of Tem cytotoxicity. These data confirm that intratumoral IL-12 plus GM-CSF induces de novo priming of tumor-specific CD8(+) T effector cells in the TDLN and establish the critical role of preexisting intratumoral CD8(+) Tem in driving this process.The Journal of Immunology 05/2009; 182(7):4217-25. · 5.52 Impact Factor
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ABSTRACT: Melanoma incidence is increasing annually and over 40,000 die of this disease each year worldwide. In this review, we discuss the rationale and recent trial results of several novel immunotherapeutic approaches and small molecule inhibitors of signalling kinases. Ipilimumab is a humanized anti-CTLA4 antibody that has been proven to increase the median overall survival of large cohorts of patients with unresectable melanoma in two phase III trials. OncoVEX(GM-CSF) is an oncolytic herpes simplex virus-1 recombined with granulocyte-macrophage colony-stimulating factor that has demonstrated durable objective responses in a phase II trial. Tumour-infiltrating lymphocytes given after lymphocyte depletion and followed by high-dose interleukin (IL)-2 yield durable complete responses in a significant percentage of melanoma patients. Lastly, denileukin diftitox, a fusion of IL-2 and diphtheria toxin, was recently observed to deplete regulatory T cells and cause durable partial responses, particularly in chemo/immune-naïve patients. These agents are enabling the rational design of novel combination trials to simultaneously increase antigen presentation, deplete regulatory T cells and block immune check-points in order to activate melanoma antigen-specific immunity. Although melanoma metastases have been found to contain thousands of mutations, the V600E BRAF mutation is clearly a driver of the neoplastic phenotype and is present in 40-60% of melanomas. Two separate small molecule antagonists of B-Raf have been found to yield very high partial response rates in metastatic melanoma, and the B-Raf inhibitor, vemurafenib (PLX4032), was recently observed to increase median overall survival in an interim analysis. However, B-Raf inhibitor resistance through up-regulation or activating mutations of alternative oncogenic signalling receptors and enzymes is proving to be a major challenge. Inhibitors of c-Kit and mitogen-activated protein kinase (MEK) have also been found to have activity against melanomas and MEK inhibitors are now being examined as a strategy to overcome B-Raf inhibitor resistance. In summary, these studies reveal that, for the first time, several immunotherapeutic and targeted agents are yielding dramatic clinical responses and improvements in overall survival in patients with unresectable stage III and IV melanoma.Drugs 07/2011; 71(10):1233-50. · 4.13 Impact Factor