Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment

Singel, Kelly L.; Emmons, Tiffany R.; Khan, Atiya; Mayor, Paul; Shen, Shichen; Wong, Jerry; Morrell, Kayla; Eng, Kevin H.; Mark, Jaron; Bankert, Richard B.; Matsuzaki, Junko; Koya, Richard C.; Blom, Anna M.; McLeish, Kenneth R.; Qu, Jun; Ram, Sanjay; Moysich, Kirsten B.; Abrams, Scott I.; Odunsi, Kunle; Zsiros, Emese; Segal, Brahm H.

doi:10.1172/jci.insight.122311

Cited by 102 publications

(109 citation statements)

References 79 publications

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“…Neither was affected by TAT‐SNAP‐23 treatment, indicating that the conditions for intraphagosomal bacterial killing remain intact. In vitro studies using TAT‐SNAP‐23 and TAT‐STX‐4 also showed that exocytosis regulates neutrophil killing of Listeria monocytogenes and plays a role in T‐cell suppression by neutrophils in ovarian cancer . A previous study showed that TAT‐fusion proteins readily entered neutrophils, but the majority of ingested protein were degraded in an endosomal compartment .…”

Section: Targeting Granule Trafficking and Docking To Inhibit Neutropmentioning

confidence: 98%

“…In vitro studies using TAT-SNAP-23 and TAT-STX-4 also showed that exocytosis regulates neutrophil killing of Listeria monocytogenes and plays a role in T-cell suppression by neutrophils in ovarian cancer. 223,224 A previous study showed that TAT-fusion proteins readily entered neutrophils, but the majority of ingested protein were degraded in an endosomal compartment. 225 Although this intracellular degradation could significantly impact dosing in vivo, an optimal concentration for in vitro studies and effective in vivo dose remain remarkably constant for multiple preparations of both fusion proteins.…”

Section: Peptide Inhibitors Of Snare Interactionsmentioning

confidence: 99%

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Therapeutic targeting of neutrophil exocytosis

Catz

McLeish

2020

Journal of Leukocyte Biology

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Dysregulation of neutrophil activation causes disease in humans. Neither global inhibition of neutrophil functions nor neutrophil depletion provides safe and/or effective therapeutic approaches. The role of neutrophil granule exocytosis in multiple steps leading to recruitment and cell injury led each of our laboratories to develop molecular inhibitors that interfere with specific molecular regulators of secretion. This review summarizes neutrophil granule formation and contents, the role granule cargo plays in neutrophil functional responses and neutrophil‐mediated diseases, and the mechanisms of granule release that provide the rationale for development of our exocytosis inhibitors. We present evidence for the inhibition of granule exocytosis in vitro and in vivo by those inhibitors and summarize animal data indicating that inhibition of neutrophil exocytosis is a viable therapeutic strategy.

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Section: Targeting Granule Trafficking and Docking To Inhibit Neutropmentioning

confidence: 98%

Section: Peptide Inhibitors Of Snare Interactionsmentioning

confidence: 99%

Therapeutic targeting of neutrophil exocytosis

Catz

McLeish

2020

Journal of Leukocyte Biology

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“…While PMN-MDSCs were originally described as a subpopulation of immature myeloid cells capable of suppressing immune responses, mature neutrophils also have the ability to limit T cell activity and promote immune evasion ( 28 , 57 ), but only upon cellular activation ( 56 , 58 ). Thus the functional similarities between PMN-MDSCs and neutrophils further complicate the differentiation between the two populations.…”

Section: Role Of Neutrophils In Tumor Progressionmentioning

confidence: 99%

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

et al. 2020

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Over the last decades, cancer immunotherapies such as checkpoint blockade and adoptive T cell transfer have been a game changer in many aspects and have improved the treatment for various malignancies considerably. Despite the clinical success of harnessing the adaptive immunity to combat the tumor, the benefits of immunotherapy are still limited to a subset of patients and cancer types. In recent years, neutrophils, the most abundant circulating leukocytes, have emerged as promising targets for anti-cancer therapies. Traditionally regarded as the first line of defense against infections, neutrophils are increasingly recognized as critical players during cancer progression. Evidence shows the functional plasticity of neutrophils in the tumor microenvironment, allowing neutrophils to exert either pro-tumor or anti-tumor effects. This review describes the tumor-promoting roles of neutrophils, focusing on their myeloid-derived suppressor cell activity, as well as their role in tumor elimination, exerted mainly via antibody-dependent cellular cytotoxicity. We will discuss potential approaches to therapeutically target neutrophils in cancer. These include strategies in humans to either silence the pro-tumor activity of neutrophils, or to activate or enhance their anti-tumor functions. Redirecting neutrophils seems a promising approach to harness innate immunity to improve treatment for cancer patients.

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“…Although a complete overview of how these immunosuppressive cells exactly contribute to resistance against immunotherapy is still lacking, several underlying mechanisms have been described in detail (Figure 1). Firstly, the expression of ICs (including PD-L1 and CTLA-4) at the surface of these immune suppressive cells provides them with the means to inhibit local T cell activation directly [46,48,53,54]. Additionally, immunosuppressive mediators produced by these cells, including IL-10 and TGF-β, can enhance the establishment of a local network of immunosuppressive cells in the TME.…”

Section: Tumor Cell Extrinsic Primary Resistance Mechanismsmentioning

confidence: 99%

Future Challenges in Cancer Resistance to Immunotherapy

Elsas

Hall

Burg

2020

Cancers

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Cancer immunotherapies, including checkpoint inhibitors, adoptive T cell transfer and therapeutic cancer vaccines, have shown promising response rates in clinical trials. Unfortunately, there is an increasing number of patients in which initially regressing tumors start to regrow due to an immunotherapy-driven acquired resistance. Studies on the underlying mechanisms reveal that these can be similar to well-known tumor intrinsic and extrinsic primary resistance factors that precluded the majority of patients from responding to immunotherapy in the first place. Here, we discuss primary and secondary immune resistance and point at strategies to identify potential new mechanisms of immune evasion. Ultimately, this may lead to improved immunotherapy strategies with improved clinical outcomes.

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Mature neutrophils suppress T cell immunity in ovarian cancer microenvironment

Cited by 102 publications

References 79 publications

Therapeutic targeting of neutrophil exocytosis

Therapeutic targeting of neutrophil exocytosis

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

Future Challenges in Cancer Resistance to Immunotherapy

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