β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells

Mohammadpour, Hemn; MacDonald, Cameron R.; Qiao, Guanxi; Chen, Minhui; Dong, Bowen; Hylander, Bonnie L.; McCarthy, Philip L.; Abrams, Scott I.; Repasky, Elizabeth A.

doi:10.1172/jci129502

Cited by 169 publications

(190 citation statements)

References 53 publications

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“…Macrophages have previously been shown to be regulated by adrenergic stress 56,57 and M2 macrophages in particular have been linked to enhanced immunosuppression [39][40][41] . This is consistent with our other data that the blockade of adrenergic stress suppresses the recruitment, survival, and function of myeloid-derived suppressor cells (MDSCs) and reduces the frequency of intratumoral regulatory T cells (Tregs) 29,32,58 . Thus, the combination of enhanced activity of CD8 + T cells combined with reduced immunosuppression in mice resulting from reduced β-AR signaling could result in a major tilt of the immune balance toward systemic tumor eradication following local radiation.…”

Section: Discussionsupporting

confidence: 93%

“…Thus, to investigate whether β-AR blockade affects metastases after radiation to the primary tumor, we employed the 4T1-Luc model to repeat the experiment with the treatment of Prop and radiation. 4T1 tumors exhibit metastatic spread to the lungs following their orthotopic implantation to the mammary glands of mice 32,51 . As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, our lab discovered that this chronic stress suppresses baseline anti-tumor immunity and accelerates tumor growth and metastasis 28,29 , while it also suppresses graft versus host disease following allogeneic hematopoietic stem cell transplantation 30,31 . When tumor-bearing mice are housed at their thermoneutral temperature (~30°C), chronic adrenergic stress and norepinephrine production are significantly lowered, CD8 + T cell-dependent responses are significantly improved, while numbers and activities of immunosuppressive cells are reduced 29,32,33 . Alternatively, when β2adrenergic receptor (AR) knockout (KO) mice were used, or if wildtype (WT) mice housed at 22°C were given the pan-β-AR blocker propranolol, we observed a similar improvement in tumor growth control and increased CD8 + T cell infiltration was seen in mice housed at 30°C 22,29,34 , suggesting that cool housing-induced adrenergic stress exerts its negative effects on the anti-tumor immune system through activation of β-ARs on immune cells.…”

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confidence: 99%

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Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

et al. 2020

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The abscopal effect following ionizing radiation therapy (RT) is considered to be a rare event. This effect does occur more frequently when combined with other therapies, including immunotherapy. Here we demonstrate that the frequency of abscopal events following RT alone is highly dependent upon the degree of adrenergic stress in the tumor-bearing host. Using a combination of physiologic, pharmacologic and genetic strategies, we observe improvements in the control of both irradiated and non-irradiated distant tumors, including metastatic tumors, when adrenergic stress or signaling through β-adrenergic receptor is reduced. Further, we observe cellular and molecular evidence of improved, antigen-specific, anti-tumor immune responses which also depend upon T cell egress from draining lymph nodes. These data suggest that blockade of β2 adrenergic stress signaling could be a useful, safe, and feasible strategy to improve efficacy in cancer patients undergoing radiation therapy.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

et al. 2020

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“…Interestingly, TGF-β-produced by MDSCs promotes the expression of programmed cell death-1 (PD1) in T cells (93). Similarly, MDSCs can hinder T cell fitness and function by directly binding FASL and PDL1 with respective death receptor ligands expressed on T cell surface (94,95). In this context, for example, the β2 adrenergic receptor triggering induces STAT3-mediated up-regulation of death receptor ligands in MDSCs, potentiating their T cell dysfunction abilities (95).…”

Section: Mdscs Promote Primary Tumor Growth and Local Invasionmentioning

confidence: 99%

“…Similarly, MDSCs can hinder T cell fitness and function by directly binding FASL and PDL1 with respective death receptor ligands expressed on T cell surface (94,95). In this context, for example, the β2 adrenergic receptor triggering induces STAT3-mediated up-regulation of death receptor ligands in MDSCs, potentiating their T cell dysfunction abilities (95). Notably, the transcriptional expression of PDL1 in MDSCs is strictly controlled by TDSFs such as vascular endothelial growth factor (VEGF) and macrophages colony-stimulating factor (M-CSF) (96) as well as by hypoxia-inducible factor (HIF-)1α signaling pathway (97).…”

Section: Mdscs Promote Primary Tumor Growth and Local Invasionmentioning

confidence: 99%

The Engagement Between MDSCs and Metastases: Partners in Crime

et al. 2020

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Tumor metastases represent the major cause of cancer-related mortality, confirming the urgent need to identify key molecular pathways and cell-associated networks during the early phases of the metastatic process to develop new strategies to either prevent or control distal cancer spread. Several data revealed the ability of cancer cells to establish a favorable microenvironment, before their arrival in distant organs, by manipulating the cell composition and function of the new host tissue where cancer cells can survive and outgrow. This predetermined environment is termed "pre-metastatic niche" (pMN). pMN development requires that tumor-derived soluble factors, like cytokines, growth-factors and extracellular vesicles, genetically and epigenetically reprogram not only resident cells (i.e., fibroblasts) but also non-resident cells such as bone marrow-derived cells. Indeed, by promoting an "emergency" myelopoiesis, cancer cells switch the steady state production of blood cells toward the generation of pro-tumor circulating myeloid cells defined as myeloid-derived suppressor cells (MDSCs) able to sustain tumor growth and dissemination. MDSCs are a heterogeneous subset of myeloid cells with immunosuppressive properties that sustain metastatic process. In this review, we discuss current understandings of how MDSCs shape and promote metastatic dissemination acting in each fundamental steps of cancer progression from primary tumor to metastatic disease.

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NNK from tobacco smoking enhances pancreatic cancer cell stemness and chemoresistance by creating a β2AR‐Akt feedback loop that activates autophagy

et al. 2022

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Low responsiveness to chemotherapy is an important cause of poor prognosis in pancreatic cancer. Smoking is a high‐risk factor for pancreatic cancer and cancer resistance to gemcitabine; however, the underlying mechanisms remain unclear. 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) is the main metabolite of tobacco burning and has been shown to be associated with cancer development and chemoresistance. However, in pancreatic cancer, its mechanism remains poorly understood. In this study, we found that NNK promoted stemness and gemcitabine resistance in pancreatic cancer cell lines. Moreover, NNK increased autophagy and elevated the expression levels of the autophagy‐related markers autophagy‐related gene 5 (ATG5), autophagy‐related gene 7 (ATG7), and Beclin1. Furthermore, the results showed that NNK‐promoted stemness and gemcitabine resistance was partially dependent on the role of NNK in cell autophagy, which is mediated by the β2‐adrenergic receptor (β2AR)‐Akt axis. Finally, we proved that NNK intervention could not only activate β2AR, but also increase its expression, making β2AR and Akt form a feedback loop. Overall, these findings show that the NNK‐induced β2AR‐Akt feedback loop promotes stemness and gemcitabine resistance in pancreatic cancer cells.

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β2 adrenergic receptor–mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells

Cited by 169 publications

References 53 publications

Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

Adrenergic stress constrains the development of anti-tumor immunity and abscopal responses following local radiation

The Engagement Between MDSCs and Metastases: Partners in Crime

NNK from tobacco smoking enhances pancreatic cancer cell stemness and chemoresistance by creating a β2AR‐Akt feedback loop that activates autophagy

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