γδ cells and tumor microenvironment: A helpful or a dangerous liason?

Presti, Elena Lo; Mitri, Roberto Di; Pizzolato, Gabriele; Mocciaro, Filippo; Dieli, Francesco; Meraviglia, Serena

doi:10.1002/jlb.5mr0717-275rr

Cited by 19 publications

(11 citation statements)

References 83 publications

(131 reference statements)

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“…74 However, their role is controversial, 75 76 possibly due to the heterogeneity of the BC microenvironment that, depending on the immune contexture, oncogenic signaling and cytokine milieu, can polarize γδ T cells toward an anti-tumoral or pro-tumoral phenotype. 77 78 The question of whether the IL30 low TME can shape cytotoxic on October 24, 2021 by guest. Protected by copyright.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome

Sorrentino

Ciummo

D'Antonio

et al. 2021

J Immunother Cancer

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BackgroundBreast cancer (BC) progression to metastatic disease is the leading cause of death in women worldwide. Metastasis is driven by cancer stem cells (CSCs) and signals from their microenvironment. Interleukin (IL) 30 promotes BC progression, and its expression correlates with disease recurrence and mortality. Whether it acts by regulating BCSCs is unknown and could have significant therapeutic implications.MethodsHuman (h) and murine (m) BCSCs were tested for their production of and response to IL30 by using flow cytometry, confocal microscopy, proliferation and sphere-formation assays, and PCR array. Immunocompetent mice were used to investigate the role of BCSC-derived IL30 on tumor development and host outcome. TCGA PanCancer and Oncomine databases provided gene expression data from 1084 and 75 hBC samples, respectively, and immunostaining unveiled the BCSC microenvironment.ResultshBCSCs constitutively expressed IL30 as a membrane-anchored glycoprotein. Blocking IL30 hindered their proliferation and self-renewal efficiency, which were boosted by IL30 overexpression. IL30 regulation of immunity gene expression in human and murine BCSCs shared a significant induction of IL23 and CXCL10. Both immunoregulatory mediators stimulated BCSC proliferation and self-renewal, while their selective blockade dramatically hindered IL30-dependent BCSC proliferation and mammosphere formation. Orthotopic implantation of IL30-overexpressing mBCSCs, in syngeneic mice, gave rise to poorly differentiated and highly proliferating MYC+KLF4+LAG3+ tumors, which expressed CXCL10 and IL23, and were infiltrated by myeloid-derived cells, Foxp3+ T regulatory cells and NKp46+RORγt+ type 3 innate lymphoid cells, resulting in increased metastasis and reduced survival. In tumor tissues from patients with BC, expression of IL30 overlapped with that of CXCL10 and IL23, and ranked beyond the 95th percentile in a Triple-Negative enriched BC collection from the Oncomine Platform. CIBERSORTx highlighted a defective dendritic cell, CD4+ T and γδ T lymphocyte content and a prominent LAG3 expression in IL30highversus IL30low human BC samples from the TCGA PanCancer collection.ConclusionsConstitutive expression of membrane-bound IL30 regulates BCSC viability by juxtacrine signals and via second-level mediators, mainly CXCL10 and IL23. Their autocrine loops mediate much of the CSC growth factor activity of IL30, while their paracrine effect contributes to IL30 shaping of immune contexture. IL30-related immune subversion, which also emerged from computational analyses, strongly suggests that targeting IL30 can restrain the BCSC compartment and counteract BC progression.

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Section: Discussionmentioning

confidence: 99%

Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome

Sorrentino

Ciummo

D'Antonio

et al. 2021

J Immunother Cancer

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“…Bisphosphonates such as zoledronate have been administered to patients alongside IL-2 to successfully expand tumoricidal Vd2 + cells in cases of lymphoma (86), prostate cancer (87), and breast cancer (88). Evidence suggests that the effectiveness of gd T cells in The Journal of Immunology tumor cell killing is highest in the acute phase, during which IFN-g-secreting gd T cells are initially recruited to the tumor microenvironment (89). S. aureus bacteremia, like early tumor development, is an acute condition in which IFN-g correlates with protection (10,11).…”

Section: Downloaded Frommentioning

confidence: 99%

Activation of Human Vδ2+ γδ T Cells by Staphylococcus aureus Promotes Enhanced Anti-Staphylococcal Adaptive Immunity

Cooper

Lalor

McLoughlin

2020

The Journal of Immunology

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Murine studies have shown the potential for gd T cells to mediate immunity to Staphylococcus aureus in multiple tissue settings by the secretion of diverse cytokines. However, the role played by gd T cells in human immune responses to S. aureus is almost entirely unknown. In this study, we establish the capacity of human Vd2 + gd T cells for rapid activation in response to S. aureus. In coculture with S. aureus-infected monocyte-derived dendritic cells (DCs), Vd2 + cells derived from peripheral blood rapidly upregulate CD69 and secrete high levels of IFN-g. DCs mediate this response through direct contact and IL-12 secretion. In turn, IFN-g released by Vd2 + cells upregulates IL-12 secretion by DCs in a positive feedback loop. Furthermore, coculture with gd T cells results in heightened expression of the costimulatory molecule CD86 and the lymph node homing molecule CCR7 on S. aureus-infected DCs. In cocultures of CD4 + T cells with S. aureus-infected DCs, the addition of gd T cells results in heightened CD4 + T cell activation. Our findings identify gd T cells as potential key players in the early host response to S. aureus during bloodstream infection, promoting enhanced responses by both innate and adaptive immune cell populations, and support their consideration in the development of host-directed anti-S. aureus treatments.

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“…Nonetheless, recent flow cytometry or immunohistochemical studies of tumor-infiltrating γδ T cells have failed to provide clear-cut evidence that they correlate positively or not with tumor growth, or even fail to correlate with any prognostic feature in different types of cancer, as reviewed in Ref. ( 61 ).…”

Section: Effects Of the Tme On γδ T Cellsmentioning

confidence: 99%

γδ T Cells and Tumor Microenvironment: From Immunosurveillance to Tumor Evasion

et al. 2018

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γδ T cells possess cytotoxic antitumor activity mediated by production of proinflammatory cytokines, direct cytotoxic activity, and regulation of the biological functions of other cell types. Hence, these features have prompted the development of therapeutic strategies in which γδ T cells agonists or ex vivo-expanded γδ T cells are administered to tumor patients. Several studies have shown that γδ T cells are an important component of tumor-infiltrating lymphocytes in patients affected by different types of cancer and a recent analysis of ~18,000 transcriptomes from 39 human tumors identified tumor-infiltrating γδ T cells as the most significant favorable cancer-wide prognostic signature. However, the complex and intricate interactions between tumor cells, tumor microenvironment (TME), and tumor-infiltrating immune cells results in a balance between tumor-promoting and tumor-controlling effects, and γδ T cells functions are often diverted or impaired by immunosuppressive signals originating from the TME. This review focuses on the dangerous liason between γδ T cells and tumoral microenvironment and raises the possibility that strategies capable to reduce the immunosuppressive environment and increase the cytotoxic ability of γδ T cells may be the key factor to improve their utilization in tumor immunotherapy.

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γδ cells and tumor microenvironment: A helpful or a dangerous liason?

Cited by 19 publications

References 83 publications

Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome

Interleukin-30 feeds breast cancer stem cells via CXCL10 and IL23 autocrine loops and shapes immune contexture and host outcome

Activation of Human Vδ2+ γδ T Cells by Staphylococcus aureus Promotes Enhanced Anti-Staphylococcal Adaptive Immunity

γδ T Cells and Tumor Microenvironment: From Immunosurveillance to Tumor Evasion

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