Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here, we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in patients with non-small cell lung cancer (NSCLC). We found a strong correlation between CD68 TAM immunostaining and PET 18 fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of patients with NSCLC. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 patients with NSCLC from The Cancer Genome Atlas database. TAM secreted TNFa to promote tumor cell glycolysis, whereas increased AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed deathligand 1 (PD-L1) expression in aerobic cancer cells as well as T-cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies, which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies, including immunotherapy. Significance: These findings show that tumor-associated macrophages can significantly modulate tumor metabolism, hindering the efficacy of anticancer therapies, including anti-PD-L1 immunotherapy.

No abstract

IntroductionInitial lactate level, lactate clearance, C-reactive protein, and procalcitonin in critically ill patients with sepsis are associated with hospital mortality. However, no study has yet discovered which factor is most important for mortality in severe sepsis patients with lactic acidosis. We sought to clarify this issue in patients with lactic acidosis who were supplementing with sodium bicarbonate.Materials and MethodsData were collected from a single center between May 2011 and April 2014. One hundred nine patients with severe sepsis and lactic acidosis who were supplementing with sodium bicarbonate were included.ResultsThe 7-day mortality rate was 71.6%. The survivors had higher albumin levels and lower SOFA, APACHE II scores, vasopressor use, and follow-up lactate levels at an elapsed time after their initial lactate levels were checked. In particular, a decrement in lactate clearance of at least 10% for the first 6 hours, 24 hours, and 48 hours of treatment was more dominant among survivors than non-survivors. Although the patients who were treated with broad-spectrum antibiotics showed higher illness severity than those who received conventional antibiotics, there was no significant mortality difference. 6-hour, 24-hour, and 48-hour lactate clearance (HR: 4.000, 95% CI: 1.309–12.219, P = 0.015) and vasopressor use (HR: 4.156, 95% CI: 1.461–11.824, P = 0.008) were significantly associated with mortality after adjusting for confounding variables.ConclusionsLactate clearance at a discrete time point seems to be a more reliable prognostic index than initial lactate value in severe sepsis patients with lactic acidosis who were supplementing with sodium bicarbonate. Careful consideration of vasopressor use and the initial application of broad-spectrum antibiotics within the first 48 hours may be helpful for improving survival, and further study is warranted.

Recent advancement in the radiotherapy technology has allowed conformal delivery of high doses of ionizing radiation precisely to the tumors while sparing large volume of the normal tissues, which have led to better clinical responses. Despite this technological advancement many advanced tumors often recur and they do so within the previously irradiated regions. How could tumors recur after receiving such high ablative doses of radiation? In this review, we outlined how radiation can elicit anti-tumor responses by introducing some of the cytokines that can be induced by ionizing radiation. We then discuss how tumor hypoxia, a major limiting factor responsible for failure of radiotherapy, may also negatively impact the anti-tumor responses. In addition, we highlight how there may be other populations of immune cells including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) that can be recruited to tumors interfering with the anti-tumor immunity. Finally, the impact of irradiation on tumor hypoxia and the immune responses according to different radiotherapy regimen is also delineated. It is indeed an exciting time to see that radiotherapy is being combined with immunotherapy in the clinic and we hope that this review can add an excitement to the field.

No abstract