Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity

Gershkovitz, Maya; Fainsod-Levi, Tanya; Khawaled, Saleh; Shaul, Merav E.; Sionov, Ronit Vogt; Cohen-Daniel, Leonor; Aqeilan, Rami I.; Shaul, Yoav D.; Fridlender, Zvi G.; Granot, Zvi

doi:10.1158/0008-5472.can-18-0540

Cited by 30 publications

(27 citation statements)

References 52 publications

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“…Recently, it was discovered that H 2 O 2 secreted by neutrophils induces a lethal influx of Ca 2+ in tumor cells which is mediated by the transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a ubiquitously expressed H 2 O 2 -dependent Ca 2+ -permeable channel that is frequently upregulated in cancer (16). Interestingly, the expression of TRPM2 (and thus the sensitivity to neutrophil killing) is up-regulated during the epithelial-to-mesenchymal transition (EMT), rendering mesenchymal cells more susceptible to neutrophil cytotoxicity, while cells expressing lower levels of TRPM2, as observed during mesenchymal-to-epithelial transition (MET), are protected from neutrophil killing (17). In addition to the H 2 O 2 -dependent “spontaneous” cytotoxicity, neutrophils are potent mediators of Fc receptor-dependent antibody-dependent cellular cytotoxicity (ADCC) against antibody-opsonized tumor cells [discussed in (7)].…”

Section: Introductionmentioning

confidence: 99%

Regulatory Interactions Between Neutrophils, Tumor Cells and T Cells

et al. 2019

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Apart from their activity in combating infections, neutrophils play an important role in regulating the tumor microenvironment. Neutrophils can directly kill (antibody-coated) cancer cells, and support other immune anti-tumoral strategies. On the other hand, neutrophils can also exert pro-tumorigenic activities via the production of factors which promote cancer growth, angiogenesis and metastasis formation. The balance of anti- and pro-cancer activity is influenced by the particularly delicate interplay that exists between neutrophils and T lymphocytes. In murine models, it has been reported that γδ T cells are a major source of IL-17 that drives the recruitment and pro-tumorigenic differentiation of neutrophils. This, however, contrasts with the well-studied anti-tumor activity of γδ T cells in experimental models and the anti-tumor activity of human γδ T cells. In this article, we first review the reciprocal interactions between neutrophils, tumor cells and T lymphocytes with a special focus on their interplay with γδ T cells, followed by the presentation of our own recent results. We have previously shown that zoledronic acid (ZOL)-activated neutrophils inhibit γδ T-cell proliferation due to the production of reactive oxygen species, arginase-1 and serine proteases. We now demonstrate that killing of ductal pancreatic adenocarcinoma (PDAC) cells by freshly isolated resting human γδ T cells was reduced in the presence of neutrophils and even more pronounced so after activation of neutrophils with ZOL. In contrast, direct T-cell receptor-dependent activation by γδ T cell-specific pyrophosphate antigens or by bispecific antibodies enhanced the cytotoxic activity and cytokine/granzyme B production of resting human γδ T cells, thereby overriding the suppression by ZOL-activated neutrophils. Additionally, the coculture of purified neutrophils with autologous short-term expanded γδ T cells enhanced rather than inhibited γδ T-cell cytotoxicity against PDAC cells. Purified neutrophils alone also exerted a small but reproducible lysis of PDAC cells which was further enhanced in the presence of γδ T cells. The latter set-up was associated with improved granzyme B and IFN-γ release which was further increased in the presence of ZOL. Our present results demonstrate that the presence of neutrophils can enhance the killing capacity of activated γδ T cells. We discuss these results in the broader context of regulatory interactions between neutrophils and T lymphocytes.

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Section: Introductionmentioning

confidence: 99%

Regulatory Interactions Between Neutrophils, Tumor Cells and T Cells

et al. 2019

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“…180 On the other hand, TANs are protective against selected tumor types or more broadly during early phases of carcinogenesis via multiple mechanisms such as stimulation of T cell-mediated immunity, [181][182][183] antigen presentation, 182 or direct killing of neoplastic cells. 184,185 The disparate roles of neutrophils in cancer reflect the extent to which these cells can adapt to developmental, anatomical, and disease-associated cues, integrating external signals into specific epigenomic and transcriptional programs. [186][187][188] This notion challenges the classical view of neutrophils as uncapable of complex transcriptional dynamics because of their highly condensed nucleus, limited RNA abundance, and extremely short half-life.…”

Section: De Terminants Of Neutrophil D Iver S It Y In C An Cermentioning

confidence: 99%

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

Caronni

Montaldo

Mezzanzanica

et al. 2021

Immunological Reviews

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The tumor microenvironment (TME) is a complex architecture of cells, including those of the immune system, of matrix components, and of their interactions within the unique physical traits of the cancer tissue. 1,2 Many elements influence the composition and cellular dynamics of the TME, such as the anatomical site, the type, and stage of the disease, the therapeutic regimen as well as host factors like age, sex, and comorbidities. 2 Within the extreme diversity of TMEs, parameters integrating the relative composition, spatial arrangement, and functional properties of infiltrating immune cells are useful indicators of disease progression and response to therapies. 2,3 For instance, high tumor infiltration of cytotoxic CD8 + T cells engaging inhibitory crosstalk in the TME via the programmed death (PD)1:PD-L1/PD-L2 axis often predicts efficient response to immune checkpoint blockade therapy. 3 In some cases, CD8 + T cells form organized assemblies with antigen-presenting cells such as dendritic cells (DCs), B cells, and macrophages within the tumor stroma; these so-called tertiary lymphoid structures are considered sites of efficient T-cell priming, and their presence is associated with good response to immunotherapy. 4 In this context, a subset of conventional DCs, termed cDC1, can efficiently cross-present tumor antigens for the induction of a durable immune response. 5-7 Accumulation of cDC1 at the tumor site is mediated at least in part by chemokines released by infiltrating natural killer (NK) cells, 8 a

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“…This occurred through a mechanism that involved a transient increase in Ca 2+ mobilization within cancer cells (18). TRPM2 upregulation in tumor cells occurred following an epithelial-to-mesenchymal transition (EMT) and cancer cells that have undergone an EMT were more susceptible to neutrophil-mediated killing (19). More recently, an interaction between the receptor for advanced glycation end products (RAGE), which is expressed on tumor cells, and cathepsin G present on murine neutrophils was shown to mediate in vitro tumor cell cytotoxicity in a H 2 O 2 -dependent manner (20).…”

Section: Anti-tumor Neutrophil Functionsmentioning

confidence: 99%

Neutrophils: Orchestrators of the Malignant Phenotype

2020

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Neutrophils are the first leukocytes recruited to sites of inflammation, where they execute anti-microbial functions to eliminate infectious agents. These functions include phagocytosis, release of reactive oxygen species and the formation of neutrophil extracellular traps via NETosis. Neutrophils are receiving increasing attention in the context of cancer, where these same neutrophil-associated functions are also important for modulating tumor growth and metastatic progression. Neutrophils are phenotypically heterogeneous and, depending on the context, exert anti-or pro-tumorigenic functions. Increasing evidence also suggests an important role of neutrophils and their involvement in promoting multiple steps of the metastatic cascade. The steps include: (1) local invasion and intravasation of cancer cells into circulation, (2) survival of cancer cells in the bloodstream and extravasation at a distant site, (3) early cancer cell seeding/survival, and (4) progressive growth of cancer cells to form macroscopic metastases. Although neutrophil functions designed to eliminate infectious agents can also eliminate tumor cells, their dysregulation can promote tumor growth and enable metastasis at multiple steps along the metastatic cascade. In this review, we will provide an overview of the current advances in neutrophil biology in the context of cancer. We also discuss the emerging field of immunometabolism, in which the rewiring of alternative metabolic pathways within neutrophils can impact their pro-tumorigenic/pro-metastatic functions.

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Microenvironmental Cues Determine Tumor Cell Susceptibility to Neutrophil Cytotoxicity

Cited by 30 publications

References 52 publications

Regulatory Interactions Between Neutrophils, Tumor Cells and T Cells

Regulatory Interactions Between Neutrophils, Tumor Cells and T Cells

Determinants, mechanisms, and functional outcomes of myeloid cell diversity in cancer

Neutrophils: Orchestrators of the Malignant Phenotype

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