Mechanisms of Cell-Mediated Immunosuppression and Cancer Progression in Nasopharyngeal Carcinoma

Impaired immune response has been noted in patients with nasopharyngeal carcinoma (NPC) for more than 3 decades. However, the associated mechanisms were never been explored. Regulatory T cells (Treg) play a critical role in the inhibition of self-reactive immune responses and have been implicated in the suppression of tumor-reactive effector T cells. Increased Treg in the circulation as well as infiltrating tumor nests have been demonstrated in several cancer types. Recently, increased Treg were identified in NPC patients, suggesting that Treg might act to suppress immune response in these individuals. Studies on mechanisms of Treg-induced immunosuppression were frequently frustrated by the difficulty on obtaining Treg lines which could be maintained long enough to accomplish these tasks. We have established a CD8+ Treg line, T12.8, from bone marrow aspirate of a patient with undifferentiated NPC. This Treg line can be expanded in vitro by supplying IL-2 alone. Phenotypically, T12.8 was TCRαβ+HLA-DR+CD25+CD27+CD45RA+CD62L+ CCR7+CD95+CD122+CD132+CTLA4+FoxP3+GITR+B7-H4+; constitutive production of sIL-2R, IL-10, TGF-β1, IL-8, GM-CSF and M-CSF in the culture supernatants and suppression of anti-CD3/CD28-induced allogeneic CD3+ T-cell proliferation via cell-to-cell contact were detected. Our further studies demonstrated that T12.8 also expressed CD40L, CD95L and HLA-G; secretion of soluble CD40L and CD95L but not soluble HLA-G was detected. When co-cultured with NPC cells, T12.8 induced tumor proliferation and chemoresistance. While T12.8 did not produce G-CSF, IL-6 or VEGF, a surge in these 3 cytokines was shown in tumor-T12.8 cocultures; greatly increased IL-8, GM-CSF and M-CSF were also detected. Here, we’d like to further explore the immunosuppressive as well as tumor-promoting activity of Treg in NPC. The following events involving interactions between Treg and DC or tumor cells will be investigated: (a) whether the existence of HLA-G+ Treg in bone marrow is a common feature in normal subjects or this is confined to patients with undifferentiated NPC; (b) whether monocyte-derived dendritic cells (DC) can be tolerized by T12.8; (c) whether T12.8 can promote tumor angiogenesis; (d) whether T12.8 can induce tumor radioresistance, as combined chemo-radiotherapy (CCRT) being proven to be effective for treating NPC; and (e) delineating mechanisms of T12.8-induced tumor proliferation and chemoresistance. Results obtained from this project may provide valuable insights on Treg-induced immune suppression as well as cancer progression, and may also shed important clues for generating more efficacious therapeutic strategies on cancer treatment.

Project ID:PC9902-1705
External Project ID:NSC98-2314-B182-019-MY3