Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma.

Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1ß inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.

ATM-dependent spontaneous regression of early Eµ-myc-induced murine B-cell leukemia depends on natural killer and T cells.

Mechanisms of spontaneous tumor regression have been difficult to characterize in a systematic manner due to their rare occurrence and the lack of model systems. Here, we provide evidence that early-stage B cells in Eµ-myc mice are tumorigenic and sharply regress in the periphery between 41 and 65 days of age. Regression depended on CD4(+), CD8(+), NK1.1(+) cells and the activation of the DNA damage response, which has been shown to provide an early barrier against cancer. The DNA damage response can induce ligands that enhance immune recognition. Blockade of DNAM-1, a receptor for one such ligand, impaired tumor regression. Hence, Eµ-myc mice provide a model to study spontaneous regression and possible mechanisms of immune evasion or suppression by cancer cells.

Nonhuman primate allogeneic hematopoietic stem cell transplantation by intraosseus vs intravenous injection: Engraftment, donor cell distribution, and mechanistic basis.

OBJECTIVE: The traditional intravenous (IV) route of administration for hematopoietic stem cell transplantation (HSCT) may result in inefficient placement of donor cells, possibly contributing to suboptimal engraftment and higher risk of graft-vs-host reactions. In order to perform detailed studies of engraftment and donor cell distribution in an animal model with anatomical similarity to man, we performed the first direct homing/engraftment efficiency comparison between intraosseus (IO) and IV HSCT in allogeneic nonhuman primate animal model to assess the utility and mechanism of donor cell homing after IO delivery. MATERIALS AND METHODS: Donor bone marrow (BM) cells labeled with PKH26 membrane dye were transplanted to nonmyeloablative-conditioned nonhuman primate animals. Chimerism was confirmed by polymerase chain reaction amplification of donor-specific short tandem repeat locus. RESULTS: Compared to the IO route, IV infusion trapped 2.4- to 4.8-fold more donor cells in peripheral organs, including the lung, heart, spleen, kidney, and liver. IO injection resulting in a 6.2-fold increase in donor cells retained in the BM at the site of injection and a 2.7-fold increase in donor cells retained in distant BM sites. A profile of selected cell adhesion molecules (CAMs) demonstrated that after IO HSCT, more donor cells express CAMs that could facilitate BM homing and redistribution to non-injection-side BM cavities. This change in homing efficiency may be clinically significant because IO transplantation in haploidentical recipients enhanced donor cell engraftment when compared to IV delivery. CONCLUSION: Our results suggest that IO injection enhances both homing and engraftment in nonhuman primate HSCT.

CXCR4 identifies transitional bone marrow premonocytes that replenish the mature monocyte pool for peripheral responses.

It is well established that Ly6Chi monocytes develop from common monocyte progenitors (cMoPs) and reside in the bone marrow (BM) until they are mobilized into the circulation. In our study, we found that BM Ly6Chi monocytes are not a homogenous population, as current data would suggest. Using computational analysis approaches to interpret multidimensional datasets, we demonstrate that BM Ly6Chi monocytes consist of two distinct subpopulations (CXCR4hi and CXCR4lo subpopulations) in both mice and humans. Transcriptome studies and in vivo assays revealed functional differences between the two subpopulations. Notably, the CXCR4hi subset proliferates and is immobilized in the BM for the replenishment of functionally mature CXCR4lo monocytes. We propose that the CXCR4hi subset represents a transitional premonocyte population, and that this sequential step of maturation from cMoPs serves to maintain a stable pool of BM monocytes. Additionally, reduced CXCR4 expression on monocytes, upon their exit into the circulation, does not reflect its diminished role in monocyte biology. Specifically, CXCR4 regulates monocyte peripheral cellular activities by governing their circadian oscillations and pulmonary margination, which contributes toward lung injury and sepsis mortality. Together, our study demonstrates the multifaceted role of CXCR4 in defining BM monocyte heterogeneity and in regulating their function in peripheral tissues.