Syntaphilin Regulates Neutrophil Migration in Cancer.

Pathologically activated neutrophils (PMN) with immunosuppressive activity, which are termed myeloid-derived suppressor cells (PMN-MDSC), play a critical role in regulating tumor progression. These cells have been implicated in promoting tumor metastases by contributing to premetastatic niche formation. This effect was facilitated by enhanced spontaneous migration of PMN from bone marrow to the premetastatic niches during the early-stage of cancer development. The molecular mechanisms underpinning this phenomenon remained unclear. In this study, we found that syntaphilin (SNPH), a cytoskeletal protein previously known for anchoring mitochondria to the microtubule in neurons and tumor cells, could regulate migration of PMN. Expression of SNPH was decreased in PMN from tumor-bearing mice and patients with cancer as compared with PMN from tumor-free mice and healthy donors, respectively. In Snph-knockout (SNPH-KO) mice, spontaneous migration of PMN was increased and the mice showed increased metastasis. Mechanistically, in SNPH-KO mice, the speed and distance travelled by mitochondria in PMN was increased, rates of oxidative phosphorylation and glycolysis were elevated, and generation of adenosine was increased. Thus, our study reveals a molecular mechanism regulating increased migratory activity of PMN during cancer progression and suggests a novel therapeutic targeting opportunity.

Immune suppressive activity of myeloid-derived suppressor cells in cancer requires inactivation of the type I interferon pathway.

Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically.

Analysis of classical neutrophils and polymorphonuclear myeloid-derived suppressor cells in cancer patients and tumor-bearing mice.

In this study, using single-cell RNA-seq, cell mass spectrometry, flow cytometry, and functional analysis, we characterized the heterogeneity of polymorphonuclear neutrophils (PMNs) in cancer. We describe three populations of PMNs in tumor-bearing mice: classical PMNs, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and activated PMN-MDSCs with potent immune suppressive activity. In spleens of mice, PMN-MDSCs gradually replaced PMNs during tumor progression. Activated PMN-MDSCs were found only in tumors, where they were present at the very early stages of the disease. These populations of PMNs in mice could be separated based on the expression of CD14. In peripheral blood of cancer patients, we identified two distinct populations of PMNs with characteristics of classical PMNs and PMN-MDSCs. The gene signature of tumor PMN-MDSCs was similar to that in mouse activated PMN-MDSCs and was closely associated with negative clinical outcome in cancer patients. Thus, we provide evidence that PMN-MDSCs are a distinct population of PMNs with unique features and potential for selective targeting opportunities.

Distinct Populations of Immune-Suppressive Macrophages Differentiate from Monocytic Myeloid-Derived Suppressor Cells in Cancer.

Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPß. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.

Identification of monocyte-like precursors of granulocytes in cancer as a mechanism for accumulation of PMN-MDSCs.

We have identified a precursor that differentiates into granulocytes in vitro and in vivo yet belongs to the monocytic lineage. We have termed these cells monocyte-like precursors of granulocytes (MLPGs). Under steady state conditions, MLPGs were absent in the spleen and barely detectable in the bone marrow (BM). In contrast, these cells significantly expanded in tumor-bearing mice and differentiated to polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Selective depletion of monocytic cells had no effect on the number of granulocytes in naive mice but decreased the population of PMN-MDSCs in tumor-bearing mice by 50%. The expansion of MLPGs was found to be controlled by the down-regulation of Rb1, but not IRF8, which is known to regulate the expansion of PMN-MDSCs from classic granulocyte precursors. In cancer patients, putative MLPGs were found within the population of CXCR1+CD15-CD14+HLA-DR-/lo monocytic cells. These findings describe a mechanism of abnormal myelopoiesis in cancer and suggest potential new approaches for selective targeting of MDSCs.

Fatty acid transport protein 2 reprograms neutrophils in cancer.

Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are pathologically activated neutrophils that are crucial for the regulation of immune responses in cancer. These cells contribute to the failure of cancer therapies and are associated with poor clinical outcomes. Despite recent advances in the understanding of PMN-MDSC biology, the mechanisms responsible for the pathological activation of neutrophils are not well defined, and this limits the selective targeting of these cells. Here we report that mouse and human PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2). Overexpression of FATP2 in PMN-MDSCs was controlled by granulocyte-macrophage colony-stimulating factor, through the activation of the STAT5 transcription factor. Deletion of FATP2 abrogated the suppressive activity of PMN-MDSCs. The main mechanism of FATP2-mediated suppressive activity involved the uptake of arachidonic acid and the synthesis of prostaglandin E2. The selective pharmacological inhibition of FATP2 abrogated the activity of PMN-MDSCs and substantially delayed tumour progression. In combination with checkpoint inhibitors, FATP2 inhibition blocked tumour progression in mice. Thus, FATP2 mediates the acquisition of immunosuppressive activity by PMN-MDSCs and represents a target to inhibit the functions of PMN-MDSCs selectively and to improve the efficiency of cancer therapy.

Unique pattern of neutrophil migration and function during tumor progression.

Although neutrophils have been linked to the formation of the pre-metastatic niche, the mechanism of their migration to distant, uninvolved tissues has remained elusive. We report that bone marrow neutrophils from mice with early-stage cancer exhibited much more spontaneous migration than that of control neutrophils from tumor-free mice. These cells lacked immunosuppressive activity but had elevated rates of oxidative phosphorylation and glycolysis, and increased production of ATP, relative to that of control neutrophils. Their enhanced spontaneous migration was mediated by autocrine ATP signaling through purinergic receptors. In ectopic tumor models and late stages of cancer, bone marrow neutrophils demonstrated potent immunosuppressive activity. However, these cells had metabolic and migratory activity indistinguishable from that of control neutrophils. A similar pattern of migration was observed for neutrophils and polymorphonuclear myeloid-derived suppressor cells from patients with cancer. These results elucidate the dynamic changes that neutrophils undergo in cancer and demonstrate the mechanism of neutrophils' contribution to early tumor dissemination.

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.

Multidisciplinary management of esophageal cancer.

This article reviews the current management of esophageal cancer, including staging and treatment options, as well as providing support for using multidisciplinary teams to better manage esophageal cancer patients.

Chondrosarcoma masquerading as cardiomyopathy.

A 17-year-old male patient presented to his primary care provider with heart failure symptoms and was transferred to our hospital with the diagnosis of idiopathic cardiomyopathy. His workup identified a large mediastinal mass with right ventricular outflow obstruction, which was resected. The pathology of the mass was a low-grade chondrosarcoma. The patient currently remains disease free at 4 years.

Repair of anomalous origin of right coronary artery from the left sinus of Valsalva.

Anomalous origin of the right coronary artery from the left sinus of Valsalva is a rare congenital anomaly but a relatively frequent cause of sudden death in the young. The medical records of 4 consecutive patients with this anomaly were retrospectively reviewed. The first 2 patients underwent coronary artery bypass and had early graft failure. The next 2 patients underwent coronary reimplantation and unroofing and have done well. This limited series suggests that bypass procedures used to treat anomalous origin of the right coronary artery from the left sinus of Valsalva are prone to early graft failure.

Lung cancer staging: a case for a new T definition.

BACKGROUND: The purpose of this study is to determine a more refined T definition for lung cancer staging on the basis of clinical outcomes. METHODS: The Walter Reed Army Medical Center Tumor Registry and the Thoracic Surgery Tumor Clinic files were queried for lung cancers diagnosed from 1990 to 2000. Cox regression analysis and Kaplan-Meier survival curves for tumor size were used to analyze the impact of size on survival and relative risk, and then used to redefine T. Using the new T definition, the cohort was restaged, and the two staging system survivals were compared using Cox regression analysis. RESULTS: Tumor size was documented in 439 males and 226 females. Forty-two tumors were 1.0 cm or less, 133 were between 1.01 and 2.0 cm, 133 were between 2.01 and 3.0 cm, 91 were between 3.01 and 4.0, 96 were between 4.01 and 5.0, and 166 were greater than 5.0 cm. A survival advantage was noted for smaller lesions, with 5-year survivals of 48.6%, 45.9%, 26.6%, 27.0%, 14.4%, and 11.6%, respectively. Cox regression analysis revealed increased risk at 2.0 cm (hazards ratio, 2.014; 95% confidence interval, 1.24 to 3.26), 4.0 cm (hazards ratio, 2.51; 95% confidence interval, 1.53 to 4.09), and 5.0 cm (hazards ratio, 3.14; 95% confidence interval, 1.96 to 5.02). After redefining T, the new staging system showed a better 5-year survival in each stage. CONCLUSIONS: Lung cancer tumor size criteria should be changed to include T1 tumors 2.0 cm and less; T2 tumors between 2.0 and 4.0 cm or pleural invasion of T1 tumor; T3 tumors greater than 4.0 cm or pleural invasion of T2 tumors.

Unlimited access to care: effect on racial disparity and prognostic factors in lung cancer.

STUDY OBJECTIVE: Evaluate the prognostic factors influencing lung cancer survival under a universal health care system and determine if access to care eliminates clinical outcome disparity. DESIGN: Retrospective case series review. BACKGROUND: Lung cancer survival is worse in men and in African Americans, thought to be related to poor general health in men and limited access to heath care in African Americans. The Military Health Care System, with unlimited access to care, provides an excellent setting for evaluating gender and racial disparities in lung cancer survival. METHODS: Lung cancers diagnosed at Walter Reed Army Medical Center, from 1990 to 2000, were evaluated by chart review for age, gender, race, smoking history, cancer history, histology, stage, and completeness of resection. RESULTS: Seven hundred thirteen Caucasians and 173 African Americans, 2:1 male predominance, had a 22% 5-year survival. Cox model analysis showed that male gender [hazard ratio (HR, 1.31) 95% confidence interval (95% CI), 1.02-1.68], advanced-stage disease (stage III: HR, 2.58; 95% CI, 1.57-4.26/stage IV: HR, 4.20; 95% CI, 2.51-7.41), and incomplete resection (HR, 4.06; 95% CI, 2.75-5.99) were predictors of poor outcome; whereas bronchoalveolar carcinoma features (HR, 0.35; 95% CI, 0.23-0.52) and smoking cessation >7 years (HR, 0.70; 95% CI, 0.49-0.99) were predictors of favorable outcome. No ethnic differences in survival were observed. CONCLUSIONS: No racial disparities in survival when access to medical care is universal. Male gender, incomplete resection, and advanced stage are significant predictors of poor outcome in lung cancer.

Outcomes and safety of surgical lung biopsy for interstitial lung disease.

STUDY OBJECTIVES: To determine the safety of surgical lung biopsy (SLB) in patients with interstitial lung disease (ILD), and specifically in those with idiopathic pulmonary fibrosis (IPF). DESIGN: Retrospective cohort. SETTING: Tertiary care university-affiliated military medical center. PATIENTS: Individuals undergoing SLB for suspected ILD. MEASUREMENTS AND RESULTS: We examined outcomes for subjects with a clinical diagnosis of ILD who had been designated to undergo SLB. Mortality (assessed at 30 and 90 days) following SLB represented the primary end point. Morbidity resulting from complications from SLB served as a secondary end point. The cohort included 83 patients (mean [+/- SD] age, 57.3 +/- 14.2 years; men, 57.8%). IPF was eventually diagnosed in slightly more than half of the subjects. Overall, 30-day and 90-day mortality rates were low (4.8% and 6.0%, respectively). Subjects with IPF did well with SLB (30-day mortality rate, 7.1%) and did not face a higher risk of either death or complications relative to individuals with non-IPF forms of ILD. The only predictors of perioperative mortality were either the need for mechanical ventilation (MV) at the time of SLB or being immunosuppressed prior to undergoing SLB. Excluding persons who met either criterion yielded an overall 90-day post-SLB mortality rate of 1.5% in persons with IPF. Approximately 40% of patients in whom IPF was eventually diagnosed were initially thought to have another form of ILD. CONCLUSIONS: Persons with IPF tolerate SLB well. Requiring MV or being immunosuppressed is associated with an increased risk for death following SLB. Safety concerns should not preclude referral for SLB in patients who are clinically suspected of having IPF.