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Preferential In Situ CD4⁺CD56⁺ T Cell Activation and Expansion within Human Glioblastoma

Allen Waziri^1,*, Brendan Killory^*, Alfred T. Ogden, III^*, Peter Canoll, Richard C. E. Anderson^*, Sally C. Kent, David E. Anderson and Jeffrey N. Bruce^*

^* Department of Neurological Surgery and Division of Neuropathology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, 02115

Recent evidence suggests that suppression of the cellular immune response is often attributable to populations of functionally distinct T cells that act to down-regulate Ag-specific effector T cells. Using flow cytometry, we evaluated tumor-infiltrating lymphocytes (TIL) from patients undergoing neurosurgical resection of glioblastoma multiforme (GBM), metastatic lung carcinoma, and meningioma for markers known to be expressed on immunoregulatory T cells. Ex vivo phenotypic characteristics, cellular proliferation, and cytokine expression patterns were compared between T cell subsets found in the PBMC and within TIL from fresh tumor samples. Interestingly, nearly half of all T cells infiltrating GBM specimens were CD56⁺ T cells, while much smaller percentages of similar cells were identified within metastatic lung tumors and meningiomas. CD56⁺ T cells identified within GBM were not canonical, or "invariant," NKT cells, as they demonstrated diverse TCR expression, a primarily CD4 single-positive phenotype, and lack of CD1d reactivity. The percentage of CD56⁺ T cells exhibiting evidence of proliferation within GBM was 3- to 4-fold higher than the proportion of proliferating CD56^– T cells from these lesions. In addition, direct ex vivo analysis of cytokine expression by TIL from GBM demonstrated significant numbers of IL-4/IL-13 positive cells, cytokines that are integral in the cell-mediated repression of tumor immunity in experimental models. We propose that GBM has a unique capacity to recruit and activate CD4⁺CD56⁺ T cells, a population that has not been previously described within human tumors.

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 Address correspondence and reprint requests to Dr. Allen Waziri, Columbia University, 710 West 168th Street, 4th floor, Neurological Institute, New York, NY 10032. E-mail address: aew2001{at}columbia.edu

² Abbreviations used in this paper: GBM, glioblastoma multiforme; Treg, regulatory T cell; TIL, tumor infiltrating lymphocyte; aGalCer, -galactosylceramide; NCAM, neural cell adhesion molecule.