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Central Role of Tumor-Associated CD8⁺ T Effector/Memory Cells in Restoring Systemic Antitumor Immunity¹

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214

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- 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 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 the National Institutes of Health/National Cancer Institute Grant R01-CA100656-01A1 and the New York State Office of Science Technology and Academic Research faculty recruitment award C040070 (to N.K.E.).

² Address correspondence and reprint requests to Dr. Nejat K. Egilmez and Dr. Mehmet O. Kilinc, Department of Microbiology and Immunology, University at Buffalo, 138 Farber Hall, 3435 Main Street, Buffalo, NY 14214. E-mail addresses: negilmez{at}buffalo.edu and mokilinc{at}buffalo.edu

³ Abbreviations used in this paper: TIL, tumor-infiltrating T lymphocyte; DC, dendritic cell; GKO, IFN- knockout; HA, hemagglutinin; PfKO, perforin knockout; TDLN, tumor-draining lymph node; Tem, T effector/memory cell.

⁴ The online version of this article contains supplemental material.