title: Disease relevance of T11TS-induced T-cell signal transduction through the CD2-mediated calcineurin-NFAT pathway: Perspectives in glioma immunotherapy.
abstract: Malignant glioma is the most lethal of a wide array of CNS neoplasms. Its onset and progression are markedly associated with profound immunosupression and paralysis of T-cell survival and proliferation. Myriad immunotherapeutic strategies are presently used to target such T-cell anomalies in glioma. Our recent work has highlighted use of the novel glycopeptide, the CD2 ligand, T11 target structure (T11TS) as an immunotherapeutic agent against experimentally induced glioma in rats. We have shown that T11TS causes multi-target modulation of key components of the T-cell - antigen presenting cell (APC) immunological synapse. This consequently triggers T-cell activation so as to reverse glioma-induced changes to physiological levels. T11TS administration also causes CD2 upregulation. Earlier we also found T11TS to cause enhanced proliferation of both CD4+ and CD8+ T-cells in glioma conditions. These findings led us to believe that downstream CD2-stimulated "alternative pathway" of calcineurin-NFAT could be a possible target for modulation by T11TS. In the present paper we thus show that immunotherapy with T11TS induces a multi-targeted approach towards activation of this "alternative pathway" of T-cell signaling providing an immunotherapeutic advantage against glioma. We show here that T11TS immunotherapy causes positive modulations of the CD2 pathway-associated proteins, viz., p59fyn, protein kinase C-θ (PKC-θ), calcineurin and nuclear factor for activation of T-cells (NFAT) and hint that this may accord greater survival and proliferation advantage to T-cells of the glioma-bearing animals for augmented defence against glioma. These findings help open a molecular immunotherapeutic door - one which is directed towards clinical studies for glioma-immunotherapy using T11TS.
authors.affiliation: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073 West Bengal, India; Department of Human Physiology, University of Calcutta, 92, APC Road, Kolkata 700009, India.
authors.forename: Suhnrita
authors.initials: S
authors.lastname: Chaudhuri
authors.affiliation: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073 West Bengal, India.
authors.forename: Debanjan
authors.initials: D
authors.lastname: Bhattacharya
authors.affiliation: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073 West Bengal, India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Singh
authors.affiliation: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073 West Bengal, India.
authors.forename: Saibal
authors.initials: S
authors.lastname: Moitra
authors.affiliation: Laboratory of Virology, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
authors.forename: Larance
authors.initials: L
authors.lastname: Ronsard
authors.affiliation: Department of Human Physiology, University of Calcutta, 92, APC Road, Kolkata 700009, India.
authors.forename: Tushar Kanti
authors.initials: TK
authors.lastname: Ghosh
authors.affiliation: Cellular and Molecular Immunology Laboratory, Department of Laboratory Medicine, School of Tropical Medicine, 108, C. R. Avenue, Kolkata, 700073 West Bengal, India. Electronic address: swapna.chaudhuri@gmail.com.
authors.forename: Swapna
authors.initials: S
authors.lastname: Chaudhuri
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy; D018801:CD2 Antigens / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000276:immunology / Q000628:therapy*; D007167:Immunotherapy; D007527:Isoenzymes / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D051381:Rats; D012756:Sheep; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D018801:CD2 Antigens; D007527:Isoenzymes; D050778:NFATC Transcription Factors; C489591:Prkcq protein, rat; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D019703:Calcineurin
keywords: Calcineurin (CaN); Glioma; Nuclear factor for activation of T-cells (NFAT); T-cell; T11 target structure (T11TS)