Organisms must be able to respond to low oxygen in a number of homeostatic and pathological contexts. Regulation of hypoxic responses via the hypoxia-inducible factor (HIF) is well established, but evidence indicates that other, HIF-independent mechanisms are also involved. Here, we report a hypoxic response that depends on the accumulation of lactate, a metabolite whose production increases in hypoxic conditions. We find that the NDRG3 protein is degraded in a PHD2/VHL-dependent manner in normoxia but is protected from destruction by binding to lactate that accumulates under hypoxia. The stabilized NDRG3 protein binds c-Raf to mediate hypoxia-induced activation of Raf-ERK pathway, promoting angiogenesis and cell growth. Inhibiting cellular lactate production abolishes the NDRG3-mediated hypoxia responses. Our study, therefore, elucidates the molecular basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases.

A B S T R A C T PurposeAdoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. Patients and MethodsPatients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8 ϩ -enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points. Results Thirty-four patients received unselected young TILs with a median of 8.0% CD4ϩ lymphocytes, and 35 patients received CD8ϩ -enriched TILs with a median of 0.3% CD4 ϩ lymphocytes. One month after TIL infusion, patients who received CD8 ϩ -enriched TILs had significantly fewer CD4 ϩ peripheral blood lymphocytes (P ϭ .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8 ϩ -enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P ϭ .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8ϩ -enriched TILs responded. ConclusionA randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8 ϩ -enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.

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Initial robotic operative times improved with practice rapidly and eventually became faster than those for laparoscopy. Developing both laparoscopic and robotic skills simultaneously can provide acceptable perioperative outcomes in rectal surgery. It might be suggested that in the current milieu of clashing interests between evolving technology and economic constrains, there might be advantages in embracing both approaches.