Blocking Interleukin (IL)4- and IL13-Mediated Phosphorylation of STAT6 (Tyr641) Decreases M2 Polarization of Macrophages and Protects Against Macrophage-Mediated Radioresistance of Inflammatory Breast Cancer

Rahal, Omar; Wolfe, Adam R.; Mandal, Pijus K.; Larson, Richard A.; Tin, Sanda; Jiménez, Cristina; Zhang, Dadong; Horton, Janet K.; Reuben, James M.; McMurray, John S.; Woodward, Wendy A.

doi:10.1016/j.ijrobp.2017.11.043

Cited by 111 publications

(78 citation statements)

References 34 publications

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“…These findings demonstrated that the upregulation of PD-1 on ILC2s could enhance M2-like macrophage polarization from CD14 + monocytes by facilitating the production of IL-4 and IL-13. Our findings were in line with some previous reports that IL-4 and IL-13 could mediate M2 macrophage polarization in vitro (27,28).…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies have demonstrated that IL-4 and IL-13, two canonical type 2 cytokines, could mediate M2 macrophage polarization (27,28). Considering the upregulation of IL-4 and IL-13 in PD-1 high ILC2s, we assessed the effect of ILC2 culture supernatant on the process of CD14 + monocyte polarization to M2-like macrophages in vitro.…”

Section: Pd1 High Ilc2s Enhance the Polarization Of M2-like Macrophagmentioning

confidence: 99%

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PD-1 upregulation enhances the immunosuppression of group 2 innate lymphoid cells by boosting IL-4 and IL-13 secretion in human non-small cell lung cancer

Liu¹,

Shen²,

Zhang³

et al. 2020

Preprint

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Background: There is increasing evidence that group 2 innate lymphoid cells (ILC2s) play an essential role in allergy and parasitic infection. However, the role of ILC2s in human lung cancer remains unclear. Methods: ILC2s from peripheral blood mononuclear cells (PBMCs) obtained from healthy donors (HDs) and non-small cell lung cancer (NSCLC) patients, and NSCLC tumor tissues were analyzed via multicolor flow cytometry. ILC2s or CD14 + cells were sorted by fluorescence-activated cell sorting. qPCR and flow cytometry were performed to assess the gene and protein expression of the indicated molecules. M1-like and M2-like macrophages were induced from CD14 + monocytes in vitro. Results: ILC2s were significantly more enriched in PBMCs and tumor tissues from NSCLC patients than in HDs. After screening for the main immune checkpoint molecules, we found that PD-1 was upregulated in ILC2s in NSCLC patients. Functionally, PD-1 high ILC2s from tumor tissues expressed higher levels of IL-4 and IL-13 regarding both mRNA and protein levels than PD-1 low ILC2s. Furthermore, PD-1 high ILC2s robustly boosted M2-like macrophage polarization in vitro, by secreting IL-4 and IL-13, while neutralization of IL-4 and IL-13 by antibodies abrogated M2-like macrophage polarization. Conclusion: ILC2s are enriched in NSCLC patients and upregulate PD-1 expression. Upregulation of PD-1 facilitates the immunosuppressive function of ILC2s. PD-1 high ILC2s enhance M2-like macrophage polarization by secreting IL-4 and IL-13. PD-1 acts as a positive regulator of the immunosuppressive function of ILC2s in human NSCLC.

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Section: Discussionsupporting

confidence: 93%

Section: Pd1 High Ilc2s Enhance the Polarization Of M2-like Macrophagmentioning

confidence: 99%

PD-1 upregulation enhances the immunosuppression of group 2 innate lymphoid cells by boosting IL-4 and IL-13 secretion in human non-small cell lung cancer

Liu¹,

Shen²,

Zhang³

et al. 2020

Preprint

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“…It is possible that this may be reflecting an effect on macrophage M2 polarization. 39 Interestingly, IL-4 increased in the ipilimumab treated cohort and patients experiencing this increase had a better outcome. This increase has been observed in mice treated with ipilimumab but an association with outcome is not observed after ipilimumab monotherapy.…”

Section: Discussionmentioning

confidence: 94%

Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer

et al. 2019

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Background. Immunotherapy has shown efficacy in small cell lung cancer (SCLC), but only a subset of patients benefits. Surrogate biomarkers are urgently needed. Our aim was to evaluate serum Th1, Th2, and proinflammatory cytokines in two cohorts of SCLC patients before and during treatment with chemotherapy with or without ipilimumab and to correlate them with survival. Patients and methods. Two cohorts of SCLC patients were studied: patients treated with chemotherapy (n = 47), and patients treated with chemotherapy plus ipilimumab (n = 37). Baseline, on-treatment and after-treatment serum samples were evaluated for the presence of IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IFN-gamma, TNF-alpha, GM-CSF, and Mip-1alpha using a Luminex assay. Differential changes in cytokines between cohorts were analyzed. Associations between cytokine levels and their changes with overall survival were evaluated. Results. Patients treated with ipilimumab showed a global increase of all cytokines after treatment initiation. A high level of IL-8 at baseline was associated with worse prognosis regardless of treatment. Baseline increased IL-2 levels predicted sensitivity to ipilimumab, while high IL-6 and TNF-alpha predicted resistance. An on-treatment increase in IL-4 levels in patients treated with immune-chemotherapy was associated with a better overall survival.Conclusions. The addition of ipilimumab to standard chemotherapy in SCLC modulates the serum levels of cytokines. Baseline levels and their change over time relate to overall survival. Blood-based biomarkers are convenient for patients, and our results support prospective validation of cytokines as predictive biomarkers for ipilimumab in SCLC. ARTICLE HISTORY

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“…This alteration may change radio-sensitivity of the cancer cells. M1 macrophages enhance the radio-sensitivity of BC cells, but M2 macrophages trigger radio-resistance via IL-4/IL-13-mediated STAT6 phosphorylation and M2 polarization (132,133).…”

Section: Microbe-chemo Therapiesmentioning

confidence: 99%

Microbiome and Breast Cancer: New Role for an Ancient Population

et al. 2020

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There are many risk factors associated with breast cancer (BC) such as the familial history of BC, using hormone replacement therapy, obesity, personal habits, and other clinical factors; however, not all BC cases are attributed to these risk factors. Recent researches show a correlation between patient microbiome and BC suggested as a new risk factor. The present review article aimed at evaluating the role of the microbiome as a risk factor in the occurrence of BC, investigating the proposed mechanisms of interaction between the microbiome and human genes involved in BC, and assessing the impact of the altered composition of breast, gut, and milk microbiome in the physiological status of normal breast as well as cancerous or non-cancerous breast lesions. The study also evaluated the growing evidence that these altered populations may hinder chemotherapeutic treatment. The role of microbiome in the development and maintenance of inflammation, estrogen metabolism, and epigenetic alterations was properly investigated. Finally, clinical and therapeutic applications of the microbiome-e.g., probiotics, microbiome genome modulation, and engineered microbiome enzymes in the management of BC were reviewed.

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Blocking Interleukin (IL)4- and IL13-Mediated Phosphorylation of STAT6 (Tyr641) Decreases M2 Polarization of Macrophages and Protects Against Macrophage-Mediated Radioresistance of Inflammatory Breast Cancer

Abstract: These data suggest that inhibition of M2 polarization of macrophages by PM37 can prevent radioresistance of IBC by down-regulating PRKCZ.

Cited by 111 publications

References 34 publications

PD-1 upregulation enhances the immunosuppression of group 2 innate lymphoid cells by boosting IL-4 and IL-13 secretion in human non-small cell lung cancer

PD-1 upregulation enhances the immunosuppression of group 2 innate lymphoid cells by boosting IL-4 and IL-13 secretion in human non-small cell lung cancer

Serum cytokine levels as predictive biomarkers of benefit from ipilimumab in small cell lung cancer

Microbiome and Breast Cancer: New Role for an Ancient Population

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