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Brain Microenvironment Promotes the Final Functional Maturation of Tumor-Specific Effector CD8⁺ T Cells¹

Frédérick Masson^*, Thomas Calzascia^2,*, Wilma Di Berardino-Besson^*, Nicolas de Tribolet, Pierre-Yves Dietrich^* and Paul R. Walker^3,*

^* Department of Oncology, Geneva University Hospital, Geneva, Switzerland; and Department of Neurosurgery, Geneva University Hospital, Geneva, Switzerland

During the priming phase of an antitumor immune response, CD8⁺ T cells undergo a program of differentiation driven by professional APCs in secondary lymphoid organs. This leads to clonal expansion and acquisition both of effector functions and a specific adhesion molecule pattern. Whether this program can be reshaped during the effector phase to adapt to the effector site microenvironment is unknown. We investigated this in murine brain tumor models using adoptive transfer of tumor-specific CD8⁺ T cells, and in spontaneous immune responses of patients with malignant glioma. Our data show proliferation of Ag-experienced tumor-specific T cells within the brain parenchyma. Moreover, CD8⁺ T cells further differentiated in the brain, exhibiting enhanced IFN- and granzyme B expression and induction of _E(CD103)₇ integrin. This unexpected integrin expression identified a subpopulation of CD8⁺ T cells conditioned by the brain microenvironment and also had functional consequences: _E(CD103)₇-expressing CD8⁺ T cells had enhanced retention in the brain. These findings were further investigated for CD8⁺ T cells infiltrating human malignant glioma; CD8⁺ T cells expressed _E(CD103)₇ integrin and granzyme B as in the murine models. Overall, our data indicate that the effector site plays an active role in shaping the effector phase of tumor immunity. The potential for local expansion and functional reprogramming should be considered when optimizing future immunotherapies for regional tumor control.

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 Association for International Cancer Research, Oncosuisse, Lionel Perrier Foundation, and Fondation Valeria Rossi di Montelera.

² Current address: Campbell Family Institute for Breast Cancer Research, 620 University Avenue #706, Toronto, Ontario M5G 2C1, Canada.

³ Address correspondence and reprint requests to Dr. Paul R. Walker, Division of Oncology, Geneva University Hospital, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. E-mail address: Paul.Walker{at}hcuge.ch

⁴ Abbreviations used in this paper: i.c., intracerebral; BIL, brain-infiltrating leukocyte; BM, bone marrow; BMDC, BM-derived dendritic cell; cLN, cervical lymph node; LN, lymph node; Tg, transgenic; WT, wild type; GP, glycoprotein.