Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap

In recent years, the role of neutrophils in cancer biology has been a matter of increasing interest. Many patients with advanced cancer show high levels of neutrophilia, tumor neutrophils are connected to dismal prognosis, and the neutrophil-to-lymphocyte ratio has been introduced as a significant prognostic factor for survival in many types of cancer. Neutrophils constitute an important portion of the infiltrating immune cells in the tumor microenvironment, but controversy has long surrounded the function of these cells in the context of cancer. Multiple evidences have shown that neutrophils recruited to the tumor can acquire either protumor or antitumor function. These findings have led to the identification of multiple and heterogeneous neutrophil subsets in the tumor and circulation. In addition, tumor-associated neutrophils (TANs) were shown to demonstrate functional plasticity, driven by multiple factors present in the tumor microenvironment. In this review, we examine the current knowledge on cancer-related circulating neutrophils, their source and the function of the different subtypes, both mature and immature. We then discuss the pro vs antitumor nature of TANs in cancer, their functional plasticity and the mechanisms that regulate neutrophil recruitment and polarization. Although the vast majority of the knowledge on neutrophils in cancer comes from murine studies, recent work has been done on human cancer-related neutrophils. In the final paragraphs, we expand on the current knowledge regarding the role of neutrophils in human cancer and examine the question whether cancer-related neutrophils (circulating or intratumoral) could be a new possible target for cancer immunotherapy.

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“…In a recent review, Eruslanov et al . nicely summarized the current knowledge on neutrophils in human cancer as compared to animal models.…”

Section: Introductionmentioning

confidence: 99%

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

2018

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“…Although the Trojan Horse mode of transmission is recognized, the associative processes involved in regulating the actual transfer are not clear. There are several reports about the unusual behavior of PMNs in mice during Leishmania infections (11); however, intrinsic differences in the biology of human and mouse neutrophils (12) restrict the extrapolation of the observations into the human system. Therefore, the absence of a proper animal model and the lack of human neutrophil cell lines makes research in this area more challenging and interesting from the point of view of revealing novel events during host-pathogen interactions.…”

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confidence: 99%

Leishmania donovaniInduces Autophagy in Human Blood–Derived Neutrophils

Pitale

Gendalur

Descoteaux

et al. 2019

The Journal of Immunology

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Neutrophils, the essential components of the innate immune system, are recruited in large numbers to the pathogen site of entry. Several pathogens induce neutrophil autophagy; however, function of autophagic events during Leishmania parasite infection remain unknown. In this article, we report a finding that is new, to our knowledge, of how Leishmania-induced human polymorphonuclear neutrophil (hPMN) autophagy regulates the silent mode of parasite transfer to macrophages by influencing the engulfment of infected cells. Leishmania infection induced a time-dependent autophagy increase responsive to block by 3-methyladenine but sensitive to ULK1/2 inhibition only after 3 h. This suggested the prevalence of canonical autophagy during later hours, ULK1/2 inhibition being able to block only canonical autophagy. Interaction of Rubicon and Beclin-1 at 1 h postinfection affirmed the prevalence of noncanonical autophagy during early infection. There was a reduction in macrophage uptake of parasite-exposed hPMNs treated with 3-methyladenine or ULK1/2 inhibitor, suggesting the involvement of both noncanonical and canonical autophagy in neutrophil engulfment. Autophagy inducer rapamycin augmented neutrophil engulfment by macrophages. Redistribution of hPMN surface CD47 encouraged neutrophil uptake. Activation of ERK, phosphoinositide 3-kinase, and NADPH oxidase–mediated reactive oxygen species generation were induced after parasite binding. The lpg1-knockout parasites expressing defective lipophosphoglycan did not induce autophagy, indicating that lipophosphoglycan is necessary for interaction with the neutrophils. Autophagy induction was TLR2/4 independent because the receptor blockade did not interfere with infection-induced autophagy. In summary, the engulfment of neutrophils by the macrophages was influenced by the escalation of hPMN autophagy, which is an important event during Leishmania infection.

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“…Mice are frequently the model species of choice for in vivo preclinical research, due to their relatively small size and short lifespans, and the large number of strains and large body of literature available. Nevertheless, mouse and other in vivo preclinical models differ from humans in many known and unknown details, both intrinsic (eg, genetic, immune, [159][160][161][162][163][164] surface area: volume ratio, lifespan 165 ) and extrinsic (eg, captivity, diet, history), which, depending on the research question, may substantially affect translational relevance. 166 It is critical to remember that each distinct inbred strain may respond differently to an intervention 126,167 that the same strain supplied by a different vendor (or with different gut microbiota) may respond differently, 168 and that sex differences in response may appear only in specific species or strains.…”

Section: Selection Of a Mouse Modelmentioning

confidence: 99%

Improving natural product research translation: From source to clinical trial

et al. 2019

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While great interest in health effects of natural product (NP) including dietary supplements and foods persists, promising preclinical NP research is not consistently translating into actionable clinical trial (CT) outcomes. Generally considered the gold standard for assessing safety and efficacy, CTs, especially phase III CTs, are costly and require rigorous planning to optimize the value of the information obtained. More effective bridging from NP research to CT was the goal of a Septe mber, 2018 trans disci plina ry workshop. Participants emphasized that replicability and likelihood of successful translation depend on rigor in experimental design, interpretation, and reporting across the continuum of NP research. Discussions spanned good practices for NP characterization and quality control; use and interpretation of models (computational through in vivo) with strong clinical predictive validity; controls for experimental artefacts, especially for in vitro interrogation of bioactivity and mechanisms of action; rigorous assessment and interpretation of prior research; transparency in all reporting; and prioritization of research questions. Natural product clinical trials prioritized based on rigorous, convergent supporting data and current public health needs are most likely to be informative and ultimately affect public health. Thoughtful, coordinated implementation of these practices should enhance the knowledge gained from future NP research. K E Y W O R D S clinical predictive validity, dietary supplements, model systems, rigor and replicability, value of information | 43 SORKIN et al.still provide invaluable guidance, the results of such trials are often met with concerns that different design choiceswhether of product, dose, timing, participant eligibility criteria, outcomes, etc.-might have yielded a substantially different result. Each interventional trial represents a substantial investment, with well-powered Phase III CTs typically consuming more than $10 million and many person-years. 9,10 Additionally, as time and funds are limited, and participant pools may also be constrained, a decision to invest in a CT often precludes pursuing other research questions, 11 which may provide more useful public health-relevant knowledge than an RCT with an insufficient evidence base.

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Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap

Cited by 123 publications

References 92 publications

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

Leishmania donovaniInduces Autophagy in Human Blood–Derived Neutrophils

Improving natural product research translation: From source to clinical trial

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