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

Abstract

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-gamma and granzyme B expression and induction of alpha(E)(CD103)beta(7) integrin. This unexpected integrin expression identified a subpopulation of CD8(+) T cells conditioned by the brain microenvironment and also had functional consequences: alpha(E)(CD103)beta(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 alpha(E)(CD103)beta(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.