Interleukin-15/interleukin-15R alpha complexes promote destruction of established tumors by reviving tumor-resident CD8+ T cells.

Mathieu Epardaud,Angelique Bellemare-Pelletier,Jessica A Hamerman,Shannon J Turley,Ananda W Goldrath,Roderick Bronson,Mark P Rubinstein,Ai-Ris Yonekura,Kutlu G Elpek

doi:10.1158/0008-5472.can-08-0045

Mathieu Epardaud, Angelique Bellemare-Pelletier + Show 7 more

Open Access

https://doi.org/10.1158/0008-5472.can-08-0045

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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.

Highlights

Cancer immunosurveillance is the process whereby innate and adaptive immune mechanisms suppress the growth of tumors [1, 2]
The remarkable potency of IL-15/IL-15Ra complexes could be beneficial in numerous clinical settings in which CD122+ cells serve as critical effectors in immune surveillance of solid tumors and chronic infections; this has not been formally tested to date
Stoklasek and colleagues recently reported that systemic administration of IL-15/IL-15Ra complexes could prevent transplanted B16 melanoma cells from forming tumors, whereas IL-15 alone had no effect on tumor engraftment [36], providing evidence that prophylactic administration of IL-15/IL15Ra complexes can prevent the generation of tumors

Summary

Introduction

Cancer immunosurveillance is the process whereby innate and adaptive immune mechanisms suppress the growth of tumors [1, 2]. CD8+ T cells and natural killer (NK) cells play important roles in this process by directly killing malignant cells [1, 3,4,5]. Cancer immunosurveillance is regulated by the immune system and by elements of the tumor microenvironment, including malignant cells, tumor stroma, and the vasculature [6]. Tumors can escape immunosurveillance by disabling the function of cytolytic lymphocytes and antigen-presenting cells, by preventing blood-borne lymphocytes from infiltrating malignant tissue or by inducing tolerance [1, 7, 8]. Various immunotherapeutic strategies have been developed for the treatment of human cancers.

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