Systemic chemotherapy promotes HIF-1α-mediated glycolysis and IL-17F pathways in cutaneous T-cell lymphoma.

BACKGROUND: Systemic chemotherapy is often the last resort of advanced cutaneous T-cell lymphoma (CTCL). Tumor recurrence and adverse effects of systemic chemotherapy are the main limitations.

OBJECTIVE: We aim to investigate the metabolic alterations in tumor cells after CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone) chemotherapy.

METHODS AND RESULTS: In advanced CTCL, CHOP chemotherapy has no survival benefit and the duration of response is significantly inferior to other canonical treatments. HIF-1α is significantly elevated in lesions of advanced MF patients as well as tumor cell line Hut78 and tumor xenograft mice model. CHOP therapy also increased glycolytic activities in a HIF-1α-dependent manner. In CTCL xenograft tumor mice model, lesional cells showed a significant increase in IL-17F after chemotherapy, shifting toward a Th17 phenotype, which process is also regulated by HIF-1α. Echinomycin, HIF-1α inhibitor, was co-administered in xenograft tumor mouse models with CHOP and showed a significant reduction in tumor growth.

CONCLUSION: CHOP chemotherapy promotes glycolysis and IL-17 pathways in a HIF-1α-dependent fashion. Furthermore, HIF-1α blockade is promising as an accompanying agent in systemic chemotherapy for patients with advanced CTCL.