The cellular biology underlying immune responses against brain tumors: the in vivo formation and function of immunological synapses, and the polarized secretion of effector cytokines

YANG; SANDERSON; CURTIN; PUNTEL; BARRET; KROEGER; CASTRO; LOWENSTEIN

San Diego, California, USA

Congreso; American Association for Cancer Research; 2008

The cellular biology underlying immune responses against brain tumors: the in vivo formation and function of immunological synapses, and the polarized secretion of effector cytokinesJieping Yang, Nicholas Sanderson, James F. Curtin, Mariana Puntel, Robert Barrett, Kurt M. Kroeger, Maria G. Castro and Pedro R. Lowenstein.Board of Governors’ Gene Therapeutics Research Institute, Cedars-Sinai Medical Center and Department of Medicine and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90048. Correspondence: lowensteinp@cshs.orgDespite the brain immune privilege, effective anti-tumor immune responses can be generated in a variety of brain tumor models. Our lab has recently shown that effector CD8+ T cells establish characteristic Kupfer-type and non Kupfer-type immunological synapses in vivo with adenovirus infected brain astrocytes. Furthermore, IFN-γ and granzyme-B were found to cluster in a polarized fashion at immunological synapses between CD8+ T cells and infected astrocytes. However, whether immunogical synapses exists between tumor cells and CTLs, and whether they are responsible for the clearance of tumor cells in vivo is unknown. In this study, we have developed an in vivo glioma mouse model to follow the direct antigen-specific interactions between CTLs and tumor cells. We have explored the utility of murine GL26 glioma expressing OVA to visualize specific antigen-specific cell-to-cell communication between CD8+ T cells and tumor cells in vivo. To understand the cellular and molecular basis of anti-tumor T cell responses in brain tumors we are currently characterizing the formation of tumor-antigen specific immunological synapses in vivo. We are characterizing their structure (through immunostaining for TCR, LFA-1, CD8+ T cells, and markers of tumor cells), and their capacity to segregate effector molecules to the immunological synapses. Further, we are also characterizing the molecular and cellular changes undergone by target tumor cells following T cell attack, and the potential role played therein by small Rho GTPases in mediating survival or demise of brain tumor cells. We believe that understanding the cellular and molecular basis of T cells’-brain tumor interactions will provide better ways of eliminating brain tumors by mounting a systemic anti-tumor specific immune response.This work was supported by NIH/NINDS R01 NS 054193.01; R01 NS 42893.01; U54 NS045309-01, and R21 NS047298-01 to P.R.L; R01 NS44556.01, R21-NSO54143.01; U01 NS052465.01; R03 TW006273-01 to M.G.C.