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Reversing Tumor Immune Suppression with Intratumoral IL-12: Activation of Tumor-Associated T Effector/Memory Cells, Induction of T Suppressor Apoptosis, and Infiltration of CD8⁺ T Effectors¹

Mehmet O. Kilinc^*,, Karanvir S. Aulakh^*,, Raji E. Nair^*,, Stacy A. Jones^*,, Pascale Alard, Michele M. Kosiewicz and Nejat K. Egilmez^2,*,

^* J.G. Brown Cancer Center and Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, KY 40202

A single intratumoral injection of IL-12 and GM-CSF-loaded slow-release microspheres induces T cell-dependent eradication of established primary and metastatic tumors in a murine lung tumor model. To determine how the delivery of cytokines directly to the microenvironment of a tumor nodule induces local and systemic antitumor T cell activity, we characterized therapy-induced phenotypic and functional changes in tumor-infiltrating T cell populations. Analysis of pretherapy tumors demonstrated that advanced primary tumors were infiltrated by CD4⁺ and CD8⁺ T cells with an effector/memory phenotype and CD4⁺CD25⁺Foxp3⁺ T suppressor cells. Tumor-associated effector memory CD8⁺ T cells displayed impaired cytotoxic function, whereas CD4⁺CD25⁺Foxp3⁺ cells effectively inhibited T cell proliferation demonstrating functional integrity. IL-12/GM-CSF treatment promoted a rapid up-regulation of CD43 and CD69 on CD8⁺ effector/memory T cells, augmented their ability to produce IFN-, and restored granzyme B expression. Importantly, treatment also induced a concomitant and progressive loss of T suppressors from the tumor. Further analysis established that activation of pre-existing effector memory T cells was short-lived and that both the effector/memory and the suppressor T cells became apoptotic within 4 days of treatment. Apoptotic death of pre-existing effector/memory and suppressor T cells was followed by infiltration of the tumor with activated, nonapoptotic CD8⁺ effector T lymphocytes on day 7 posttherapy. Both CD8⁺ T cell activation and T suppressor cell purge were mediated primarily by IL-12 and required IFN-. This study provides important insight into how local IL-12 therapy alters the immunosuppressive tumor milieu to one that is immunologically active, ultimately resulting in tumor regression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health/National Cancer Institute Grant R01-CA100656-01A1 (to N.K.E.).

² Address correspondence and reprint requests to Dr. Nejat Egilmez, J.G. Brown Cancer Center and Department of Microbiology and Immunology, University of Louisville, Delia Baxter Research Building, Room 119, 580 South Preston Street, Louisville, KY 40202. E-mail address: nejat.egilmez{at}louisville.edu

³ Abbreviations used in this paper: LN, lymph node; TIL, tumor-infiltrating lymphocyte; FNA, fine needle aspirate; Ct, threshold cycle; TDLN, tumor-draining LN; AICD, activation-induced cell death; FasL, Fas ligand; wt, wild type; GKO, IFN--knockout.

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