Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.

One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.

Lactate supports a metabolic-epigenetic link in macrophage polarization.

Lactate accumulation is a hallmark of solid cancers and is linked to the immune suppressive phenotypes of tumor-infiltrating immune cells. We report herein that interleukin-4 (IL-4)­induced M0 → M2 macrophage polarization is accompanied by interchangeable glucose- or lactate-dependent tricarboxylic acid (TCA) cycle metabolism that directly drives histone acetylation, M2 gene transcription, and functional immune suppression. Lactate-dependent M0 → M2 polarization requires both mitochondrial pyruvate uptake and adenosine triphosphate­citrate lyase (ACLY) enzymatic activity. Notably, exogenous acetate rescues defective M2 polarization and histone acetylation following mitochondrial pyruvate carrier 1 (MPC1) inhibition or ACLY deficiency. Lastly, M2 macrophage­dependent tumor progression is impaired by conditional macrophage ACLY deficiency, further supporting a dominant role for glucose/lactate mitochondrial metabolism and histone acetylation in driving immune evasion. This work adds to our understanding of how mitochondrial metabolism affects macrophage functional phenotypes and identifies a unique tumor microenvironment (TME)­driven metabolic-epigenetic link in M2 macrophages.

A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients.

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19-associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.

Exosomal PD-L1: Roles in Tumor Progression and Immunotherapy.

The use of immune checkpoint therapies targeting programmed death-1 (PD-1) and its ligand (PD-L1) continue to show limited durable success in clinical cases despite widespread application. While some patients achieve complete responses and disease remission, others are completely resistant to the therapy. Recent evidence in the field suggests that tumor-derived exosomes could be responsible for mediating systemic immunosuppression that antagonizes anti-PD-1 checkpoint therapy. In this Opinion article, we discuss our claim that endogenous tumor exosomal PD-L1 and tumor-derived exosome-induced PD-L1 are two of the most notable mechanisms of exosome-mediated resistance against antitumor immunity and we discuss how this resistance could directly influence immune checkpoint therapy failure.

Use of postexcision preirradiation mammography in patients with ductal carcinoma in situ of the breast treated with breast-conserving therapy.

PURPOSE: Postexcision preirradiation mammography (PPM) is frequently performed in patients with ductal carcinoma in situ (DCIS) treated with breast-conserving therapy (BCT) to evaluate for residual suspicious calcifications; but no clear evidence supports this practice. The current study was undertaken to investigate the value of PPM in the management of patients with DCIS. METHODS AND MATERIALS: We conducted a retrospective review of patients treated for DCIS with BCT at the University of Pennsylvania. The impact of PPM on surgical management and on local recurrence was evaluated. Factors associated with the use of PPM, the results of PPM, and the likelihood of finding residual malignancy at the time of re-excision in patients with PPM were also examined. RESULTS: One hundred forty-four of 281 patients (51%) underwent PPM. Of the 144 patients who received PPM, 34 (24%; 95% confidence interval, 17%-31%) had residual suspicious calcifications (a "positive PPM"). Of the 34 patients with a positive PPM, all underwent a re-excision and 19 (56%; 95% confidence interval, 35%-70%) were found to have residual malignancy. Ten of 34 patients with a positive PPM had negative margins, of which 6 had a residual malignancy. Assuming all patients with close, positive, or indeterminate surgical margins would have undergone re-excision regardless of the findings of PPM, PPM resulted in a change in surgical management in 7% (10/144) of patients and removal of residual DCIS in 4% (6/144). With a median follow-up of 9.5 years, the use of PPM was not associated with an improvement in 10-year local recurrence-free survival (94.8% vs 91.5%, P = .368). CONCLUSIONS: In this study, PPM affected surgical management in only a small percentage of patients and had no impact on local recurrence. The routine use of PPM in women undergoing BCT for DCIS may not be warranted.