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CD8-Mediated Type 1 Antitumor Responses Selectively Modulate Endogenous Differentiated and Nondifferentiated T Cell Localization, Activation, and Function in Progressive Breast Cancer¹

Mark J. Dobrzanski^2,*, Joyce B. Reome, James C. Hylind and Kathleen A. Rewers-Felkins^*

^* Texas Tech University School of Medicine, Department of Internal Medicine, Amarillo, TX 79106; and Trudeau Institute, Saranac Lake, NY 12983

CD8 T cell-mediated immune responses fall into two distinct types based on effector cell-derived cytokine production. Type I CD8 T cells (Tc1) produce IFN-, whereas type 2 cells (Tc2) secrete IL-4, IL-5, IL-10, and GM-CSF. Using a murine TCR transgenic T cell/breast tumor model, we show that adoptively transferred Ag-specific Tc1 cells are more effective in delaying mammary tumor growth and progression than that of functionally distinct Tc2 cells. Donor Tc1 cells administered 7 days posttumor challenge localized and persisted at sites of primary tumor growth with antitumor responses that were dependent, in part, on effector cell-derived IFN-. Tc1-mediated responses markedly enhanced the appearance and local accumulation of highly differentiated (CD44^high) CD4 and CD8 endogenous tumor-infiltrating T cells when compared with that of untreated tumor-bearing mice. Conversely, Tc1 cell transfer markedly delayed the appearance of corresponding nondifferentiated (CD44^low) endogenous T cells. Such cells were acutely activated as defined by coexpression of surface markers associated with TCR engagement (CD69) and early T cell activation (CD25). Moreover, cellular response kinetics appeared to further correlate with the up-regulation of endogenous T cells producing the chemokine IFN--inducible protein-10 in vivo. This suggested that CD8-mediated type 1 antitumor responses cannot only promote accumulation of distinct endogenous CD4 and CD8 T cell subpopulations, but also facilitate and preferentially modulate their localization kinetics, persistence, states of activation/differentiation, and function within the primary tumor environment at various stages of tumor progression. These studies offer insight into potential mechanisms for enhancing T cell-based immunotherapy in breast cancer.

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 U.S. Army Medical Research and Development Command Breast Cancer Research Program Grant DAMD 17-01-1-0429.

² Address correspondence and reprint requests to Dr. Mark J. Dobrzanski, Texas Tech University School Of Medicine, Department of Internal Medicine, 1400 Wallace Boulevard, Room 214, Amarillo, TX 79106. E-mail address: mark.dobrzanski{at}ttuhsc.edu

³ Abbreviations used in this paper: TIL, tumor-infiltrating T lymphocyte; FAB, fluorescent Ab buffer; HA, hemagglutinin; IP-10, IFN--inducible protein-10; Tc1, type I CD8 T cell; Tc2, type 2 CD8 T cell; WT, wild type.

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