A-105 Role of fibroblasts in HTLV-1-mediated lymphomagenesis

Only a low percentage (2%–5%) of HTLV-1-infected people develop ATLL after a very prolonged latency (2–6 decades). Besides Tax and HBZ viral products, responsible for immortalization of CD4 + T lymphocytes, and genetic and epigenetic cell abnormalities, host factors most likely contribute to the induction of the overt clinical disease. On the basis of previous in vitro studies done by other groups, we conducted in vivo experiments to investigate the role of fibroblasts, one of the major components of microenvironment, in HTLV-1-induced tumorigenesis. Primary human foreskin fibroblasts (HFF) xenotransplanted together with in vitro HTLV-1-immortalized C91/PL cells into immunodeficient Balb/c Rag2−/−ɣc−/− mice were found to significantly trigger the oncogenic potential of C91/PL cells. Cell lines established from lymphomatous masses and subsequent in vitro/in vivo passages acquired the stable property to induce aggressive T-cell lymphoma without the need of HFF support. Tumorigenic cell lines, among which C91/III cells, derived from C91/PL cells, showed no significant variation in the expression of the HTLV-1 gag, env and tax/rex mRNAs compared to C91/PL cells; in contrast, all the viral transcripts coding for the accessory proteins revealed a significant increase in C91/III cells. Moreover, these cells released higher amounts of several factors, suggesting the amplification of soluble autocrine and paracrine signals. HFF-co-cultured C91/PL cells acquired several characteristics of C91/III cells, including a more aggressive in vivo behavior. Conversely, viral transcription profile of co-cultured cells was not significantly different from that of C91/PL cells, indicating that changes in viral gene expression observed in C91/III cells were likely not responsible for the higher lymphomagenic capacity of the C91/PL-derived cell lines. These findings suggest that the crosstalk with fibroblasts may boost the tumorigenic properties of HTLV-1-immortalized T-cells through activation of autocrine and paracrine pro-lymphomagenic, stimulatory loops. These results provide new insight into ATLL pathogenic mechanisms and new potential targets for ATLL prevention.