Neutrophils suppress tumor‐infiltrating T cells in colon cancer via matrix metalloproteinase‐mediated activation of
            <scp>TGF</scp>
            β

Germann, Markus; Zangger, Nadine; Sauvain, Marc‐Olivier; Sempoux, Christine; Bowler, Amber D.; Wirapati, Pratyaksha; Kandalaft, Lana E.; Delorenzi, Mauro; Tejpar, Sabine; Coukos, George; Radtke, Freddy

doi:10.15252/emmm.201910681

Cited by 120 publications

(101 citation statements)

References 50 publications

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“…In this context, the review by Treffers et al [63] cited several early studies that showed that serine proteases cleave cytokines such as TNFα, IL-2 and IL-6, thereby impairing their functionality [63]. More recently, albeit in the setting of a murine model of colon cancer, neutrophil infiltration was most strongly associated with immunosuppression, which resulted from the release of matrix metalloproteinase 9 (MMP-9) and the resultant proteolytic activation of abundant latent TGFß in the TME [98]. With respect to clinical relevance, analysis of "two publicly available colorectal cancer gene expression datasets revealed that T cell signatures were lower in tumors with either high neutrophil or high TGFß signatures, but lowest when both neutrophil and TGFß signatures were high" [98].…”

Section: Proteasesmentioning

confidence: 99%

“…More recently, albeit in the setting of a murine model of colon cancer, neutrophil infiltration was most strongly associated with immunosuppression, which resulted from the release of matrix metalloproteinase 9 (MMP-9) and the resultant proteolytic activation of abundant latent TGFß in the TME [98]. With respect to clinical relevance, analysis of "two publicly available colorectal cancer gene expression datasets revealed that T cell signatures were lower in tumors with either high neutrophil or high TGFß signatures, but lowest when both neutrophil and TGFß signatures were high" [98]. Based on these findings, the authors proposed that T cells are excluded in TMEs in which neutrophils and TGFß are prevalent [98].…”

Section: Proteasesmentioning

confidence: 99%

“…With respect to clinical relevance, analysis of "two publicly available colorectal cancer gene expression datasets revealed that T cell signatures were lower in tumors with either high neutrophil or high TGFß signatures, but lowest when both neutrophil and TGFß signatures were high" [98]. Based on these findings, the authors proposed that T cells are excluded in TMEs in which neutrophils and TGFß are prevalent [98].…”

Section: Proteasesmentioning

confidence: 99%

“…Although unproven in the clinical setting, other potential MDSC-targeted adjunctive strategies include: (i) mAb targeting of MMP-9 [143], which promotes activation of TGFβ1 in the TME [98]; (ii) small molecule inhibitors of MDSC-derived arginase-1 (CB-1158) [144] and IDO (indoximod) [145], which may preserve arginine and tryptophan, respectively, in the TME; (iii) attenuation of activation of adenylyl cyclase in TILs using antagonists of adenosine A2 A receptors (CPI-444 and AZD4635) and ATP ectonucleotidases [146], as well as inhibitors of cyclooxygenases; and iv) pharmacological targeting of PAD4, a key enzyme in NET formation. Additionally, recent data suggest that TRAIL-R2 (an agonistic antibody of the TNF-Related Apoptosis-Inducing Ligand Receptor 2) induces death of PMN-MDSCs in vitro and also potentiates the effect of the CTLA-4-targeted immune checkpoint blockade in animal models of experimental tumorigenesis [147].…”

Section: Other Strategiesmentioning

confidence: 99%

“…Uncertain, but administration of ICD-inducing strategies may be preferable [59,137] Administration of CXCR1/2 antagonists Very promising, undergoing advanced clinical evaluation [138][139][140][141] mAb targeting of MMP-9 Unproven, but may represent an alternative strategy to prevent activation of latent TGFβ1 in the TME [98] Small molecule inhibitors of arginase-1 and IDO to preserve arginine and tryptophan, respectively, in the TME Unproven [144,145] Small molecule antagonists of adenosine A 2A receptors, as well as inhibitors of ATP ectonucleotidases and cyclooxygenases to prevent activation of T cell adenylyl cyclase via production of adenosine and PGE 2, respectively Unproven [146] Monoclonal antibody (mAb); indoleamine-2,3-dioxygenase (IDO).…”

Section: Other Strategiesmentioning

confidence: 99%

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Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

et al. 2020

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Notwithstanding the well-recognized involvement of chronic neutrophilic inflammation in the initiation phase of many types of epithelial cancers, a growing body of evidence has also implicated these cells in the pathogenesis of the later phases of cancer development, specifically progression and spread. In this setting, established tumors have a propensity to induce myelopoiesis and to recruit neutrophils to the tumor microenvironment (TME), where these cells undergo reprogramming and transitioning to myeloid-derived suppressor cells (MDSCs) with a pro-tumorigenic phenotype. In the TME, these MDSCs, via the production of a broad range of mediators, not only attenuate the anti-tumor activity of tumor-infiltrating lymphocytes, but also exclude these cells from the TME. Realization of the pro-tumorigenic activities of MDSCs of neutrophilic origin has resulted in the development of a range of adjunctive strategies targeting the recruitment of these cells and/or the harmful activities of their mediators of immunosuppression. Most of these are in the pre-clinical or very early clinical stages of evaluation. Notable exceptions, however, are several pharmacologic, allosteric inhibitors of neutrophil/MDSC CXCR1/2 receptors. These agents have entered late-stage clinical assessment as adjuncts to either chemotherapy or inhibitory immune checkpoint-targeted therapy in patients with various types of advanced malignancy. The current review updates the origins and identities of MDSCs of neutrophilic origin and their spectrum of immunosuppressive mediators, as well as current and pipeline MDSC-targeted strategies as potential adjuncts to cancer therapies. These sections are preceded by a consideration of the carcinogenic potential of neutrophils.

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Section: Proteasesmentioning

confidence: 99%

Section: Proteasesmentioning

confidence: 99%

Section: Proteasesmentioning

confidence: 99%

Section: Other Strategiesmentioning

confidence: 99%

Section: Other Strategiesmentioning

confidence: 99%

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Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

et al. 2020

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Engineering and Targeting Neutrophils for Cancer Therapy

Zhang,

Gu,

Wang

et al. 2024

Advanced Materials

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Neutrophils are the most abundant white blood cells in the circulation and act as the first line of defense against infections. Increasing evidence suggests that neutrophils possess heterogeneous phenotypes and functional plasticity in human health and diseases, including cancer. Neutrophils play multifaceted roles in cancer development and progression, and an N1/N2 paradigm of neutrophils in cancer has been proposed, where N1 neutrophils exert anti‐tumor properties while N2 neutrophils display tumor‐supportive and immune‐suppressive functions. Selective activation of beneficial neutrophil population and targeted inhibition or re‐polarization of tumor‐promoting neutrophils has shown an important potential in tumor therapy. In addition, due to the natural inflammation‐responsive and physical barrier‐crossing abilities, neutrophils and their derivatives (membranes and extracellular vesicles) are regarded as advanced drug delivery carriers for enhanced tumor targeting and improved therapeutic efficacy. In this review, we comprehensively presented the recent advances in engineering neutrophils for drug delivery and targeting neutrophils for remodeling tumor microenvironment. This review will provide a broad understanding of the potential of neutrophils in cancer therapy.This article is protected by copyright. All rights reserved

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SKAP1 Expression in Cancer Cells Enhances Colon Tumor Growth and Impairs Cytotoxic Immunity by Promoting Neutrophil Extracellular Trap Formation via the NFATc1/CXCL8 Axis

Gao,

Liu,

et al. 2024

Advanced Science

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The mechanisms underlying the development and progression of colon cancer are not fully understood. Herein, Src kinase associated phosphoprotein 1 (SKAP1), an immune cell adaptor, is identified as a novel colon cancer‐related gene. SKAP1 expression is significantly increased in colon cancer cells. High SKAP1 levels are independently predictive of poor survival in patients with colon cancer. Notably, SKAP1 expression in colon cancer cells exerted a significant tumor‐promoting effect in vivo rather than in vitro. Screening of tumor‐infiltrating immune cells revealed the involvement of neutrophils in SKAP1‐induced colon tumor promotion. Enhanced formation of neutrophil extracellular traps (NETs) is found to be a key downstream event that contributed to the pro‐tumor role of SKAP1. In colon cancer cells, SKAP1 increased the expression of C‐X‐C motif chemokine ligand 8 (CXCL8) via nuclear factor of activated T cells c1 (NFATc1). The blockade of CXCL8 or NFATc1 largely attenuated neutrophil infiltration, NET formation, and tumor promotion induced by SKAP1. Furthermore, inhibiting SKAP1‐induced NET significantly enhanced the antitumor efficiency of adoptive natural killer cell therapy in colon tumor models. In conclusion, SKAP1 significantly promotes colon cancer growth via the cancer cell/neutrophil NFATc1/CXCL8/NET axis, suggesting that SKAP1 is a potential target for colon cancer therapy.

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Neutrophils suppress tumor‐infiltrating T cells in colon cancer via matrix metalloproteinase‐mediated activation of TGF β

Cited by 120 publications

References 50 publications

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

Role of the Neutrophil in the Pathogenesis of Advanced Cancer and Impaired Responsiveness to Therapy

Engineering and Targeting Neutrophils for Cancer Therapy

SKAP1 Expression in Cancer Cells Enhances Colon Tumor Growth and Impairs Cytotoxic Immunity by Promoting Neutrophil Extracellular Trap Formation via the NFATc1/CXCL8 Axis

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