bims-stacyt Biomed News
on Paracrine crosstalk between cancer and the organism
Issue of 2020‒04‒05
four papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Cancer Immunol Res. 2020 Apr 01. pii: canimm.0360.2019. [Epub ahead of print]
    de Almeida PE, Mak J, Hernandez G, Jesudason R, Herault A, Javinal V, Borneo J, Kim JM, Walsh KB.
      Anti-angiogenic therapies that target the vascular endothelial growth factor (VEGF) pathway have been used clinically to combat cancer for over a decade. Beyond having a direct impact on blood vessel development and tumor perfusion, accumulating evidence indicates that these agents also affect antitumor immune responses. Numerous clinical trials combining anti-angiogenic drugs with immunotherapies for the treatment of cancer are ongoing, but a mechanistic understanding of how disruption of tumor angiogenesis may impact immunity is not fully discerned. Here we reveal that blockade of VEGF-A with a monoclonal antibody to VEGF augments activation of CD8+ T cells within tumors and potentiates their capacity to produce cytokines. We demonstrate that this phenomenon relies on the disruption of VEGFR2 signaling in the tumor microenvironment, but does not affect CD8+ T cells directly. Instead, the augmented functional capacity of CD8+ T cells stems from increased tumor hypoxia that initiates a hypoxia-inducible factor-1α (HIF-1α) program within CD8+ T cells that directly enhances cytokine production. Lastly, combinatorial administration of anti-VEGF with an immunotherapeutic antibody, anti-OX40, improved antitumor activity over single-agent treatments. Our findings illustrate that anti-VEGF treatment enhances CD8+ T-cell effector function and provides a mechanistic rationale for combining anti-angiogenic and immunotherapeutic drugs for cancer treatment.
  2. Mol Neurobiol. 2020 Apr 01.
    Schölwer I, Habib P, Voelz C, Rolfes L, Beyer C, Slowik A.
      Post-hypoxic/ischemic neuroinflammation is selectively driven by sterile inflammation, which implies the interplay of brain-intrinsic immune cells with other neural cells and immigrated peripheral immune cells. The resultant inflammatory cascade evolves extra- and intracellular pathogen and danger-associated receptors. The latter interacts with multiprotein complexes termed inflammasomes. The NLRP3 inflammasome is one of the best-described inflammasomes. However, its impact on post-ischemic neuroinflammation and its role in neuroprotection after ischemic stroke are still under debate. Microglial cells are known to be the main source of neuroinflammation; hence, we depleted NLRP3 in BV-2 microglial cells using shRNA to investigate its role in IL-1β maturation and phagocytosis after hypoxia (oxygen-glucose-deprivation (OGD)). We also examined the expression profiles of other inflammasomes (NLRC4, AIM2, ASC) and caspase-1 activity after OGD. OGD triggered caspase-1 activity and increased IL-1β secretion in BV-2 cells with no alteration after NLRP3 depletion. The expression of the AIM2 inflammasome was significantly higher after OGD in NLRP3-depleted cells, whereas NLRC4 was unaltered in all groups. Interestingly, OGD induced a complete inactivation of phagocytic activity in wild-type cells, while in NLRP3-depleted BV-2, this inactivity was restored after hypoxia. Our findings indicate a minor role of NLRP3 in the inflammatory response after hypoxic/ischemic stimulus. However, NLRP3 seems to play a pivotal role in the regulation of post-ischemic phagocytosis. This might be a prerequisite for the putative neuroprotective effect.
    Keywords:  AIM2; Hypoxia; Inflammasomes; NLRC4; NLRP3; Neuroinflammation; OGD; Phagocytosis
  3. Sci Rep. 2020 Mar 27. 10(1): 5555
    Sharma M, Boytard L, Hadi T, Koelwyn G, Simon R, Ouimet M, Seifert L, Spiro W, Yan B, Hutchison S, Fisher EA, Ramasamy R, Ramkhelawon B, Moore KJ.
      During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes. Evidence suggests that the rewiring of cellular metabolism can regulate macrophage function. However, the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity are poorly defined. Here, we demonstrate that ATM from obese mice exhibit metabolic profiles characterized by elevated glycolysis and oxidative phosphorylation, distinct from ATM from lean mice. Increased activation of HIF-1α in ATM of obese visceral adipose tissue resulted in induction of IL-1β and genes in the glycolytic pathway. Using a hypoxia-tracer, we show that HIF-1α nuclear translocation occurred both in hypoxic and non-hypoxic ATM suggesting that both hypoxic and pseudohypoxic stimuli activate HIF-1α and its target genes in ATM during diet-induced obesity. Exposure of macrophages to the saturated fatty acid palmitate increased glycolysis and HIF-1α expression, which culminated in IL-1β induction thereby simulating pseudohypoxia. Using mice with macrophage-specific targeted deletion of HIF-1α, we demonstrate the critical role of HIF-1α-derived from macrophages in regulating ATM accumulation, and local and systemic IL-1β production, but not in modulating systemic metabolic responses. Collectively, our data identify enhanced glycolysis and HIF-1α activation as drivers of low-grade inflammation in obesity.
  4. Mol Ther Nucleic Acids. 2020 Mar 13. pii: S2162-2531(20)30093-7. [Epub ahead of print]20 421-437
    Wang Y, Lu J, Chen L, Bian H, Hu J, Li D, Xia C, Xu H.
      Pathological angiogenesis is necessary for tumor development and metastasis. Tumor-derived extracellular vesicles (EVs) play an important role in mediating the crosstalk between cancer cells and vascular endothelial cells. To date, whether and how microRNAs (miRNAs) encapsulated in tumor-derived EVs affect angiogenesis in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we showed that miR-181b-5p, an angiogenesis-promoting miRNA of ESCC, can be transferred from ESCC cells to vascular endothelial cells via EVs. In addition, ESCC-derived EVs-miR-181b-5p dramatically induced angiogenesis by targeting PTEN and PHLPP2, and thereby facilitated tumor growth and metastasis. Moreover, miR-181b-5p was highly expressed in ESCC tissues and serum EVs. High miR-181b-5p expression level in ESCC patients was well predicted for poor overall survival. Our work suggests that intercellular crosstalk between tumor cells and vascular endothelial cells is mediated by tumor-derived EVs. miR-181b-5p-enriched EVs secreted from ESCC cells are involved in angiogenesis that control metastasis of ESCC, providing a potential diagnostic biomarker or drug target for ESCC patients.
    Keywords:  angiogenesis; esophageal squamous cell carcinoma; extracellular vesicle; metastasis; miR-181b-5p; prognosis