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Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils., Significance: Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells.

SummaryHypothesisNon-small cell lung cancer (NSCLC) is the leading cause of cancer mortality. Recent retrospective clinical analyses suggest that blocking the receptor activator of NF-κB (RANK) signaling pathway inhibits the growth of NSCLC and might represent a new treatment strategy.MethodsRANK and RANKL expression in human lung adenocarcinoma was interrogated from publicly available gene expression datasets. Several genetically engineered mouse models were used to evaluate treatment efficacy of RANK-Fc to block RANKL, with primary tumor growth measured longitudinally using micro-computed tomography. A combination of RANKL blockade with cisplatin was tested to mirror an ongoing clinical trial.ResultsIn human lung adenocarcinoma datasets, RANKL expression was associated with decreased survival and KRAS mutation, with the highest levels in tumors with co-occurring KRAS and LKB1 mutations. In KrasLSL-G12D/WT, KrasLSL-G12D/WT; Lkb1Flox/Flox and KrasLSL-G12D/WT; p53Flox/Flox mouse models of lung adenocarcinoma, we monitored an impaired progression of tumors upon RANKL blockade. Despite elevated expression of RANKL and RANK in immune cells, treatment response was not associated with major changes in the tumor immune microenvironment. Combined RANK-Fc with cisplatin revealed increased efficacy compared to single agents.ConclusionsRANKL blocking agents impair the growth of primary lung tumors in several mouse models of lung adenocarcinoma, and suggest that patients with KRAS mutant lung tumors will benefit from such treatments.

With over 1.5 million deaths yearly, lung cancer has become the leading cause of cancer-related mortality worldwide. Although targeted therapies are emerging to combat non-small cell lung cancer (NSCLC), the principal type of lung cancer, they are currently limited to a small fraction of tumors with defined oncogenic alterations, and no specific treatment exists against tumors carrying activating mutations in the most frequently mutated proto-oncogene, KRAS. Here we show an association between expression of the osteoclast differentiation factor, receptor activator of NF-kappaB (RANK) ligand (RANKL) and overall survival in NSCLC, and an impaired progression of Kras-mutant tumors upon pharmacological blockade of RANKL in several genetically-engineered mouse models of NSCLC. RANKL blockade used as monotherapy led to a rapidly diminished tumor growth rate, with shrinkage in a large proportion of tumors, as monitored by in vivo micro-computed tomography. The anti-tumor response, which was characterized by apoptosis induction and NF-kappaB pathway attenuation in tumor cells, as well as increased dendritic cell maturation with proliferation of CD8+ T cells in the tumor microenvironment, lasted for a prolonged period of time without noticeable resistance. Combined administration of the standard chemotherapy cisplatin with the RANKL inhibitor to mirror an ongoing clinical trial revealed increased efficacy compared to each treatment alone. Finally, we report the case of a patient whose primary lung tumor responded to a RANKL inhibitory drug. Altogether, our results indicate that RANKL blocking agents used as monotherapies or in combination treatment impair the growth of primary lung tumors.