Neutrophils have been extensively described in the pathophysiology of autoimmune and infectious diseases. Accumulating evidence also suggests the important role of neutrophils in cancer progression through their interaction with cancer and immune cells in blood and in the tumor microenvironment (TME). Most studies have described neutrophils as key drivers of cancer progression, due to their involvement in various tumor promoting functions including proliferation, aggressiveness, and dissemination, as well as in immune suppression. However, such studies were focusing on late-stages of tumorigenesis, in which chronic inflammation had already developed. The role of tumor-associated neutrophils (TANs) at early stages of tumor development remains poorly described, though recent findings indicate that early-stage TANs may display anti-tumor properties. Beyond their role at tumor site, evidence supported by NLR retrospective studies and functional analyses suggest that blood neutrophils could also actively contribute to tumorigenesis. Hence, it appears that the phenotype and functions of neutrophils vary greatly during tumor progression, highlighting their heterogeneity. The origin of pro- or anti-tumor neutrophils is generally believed to arise following a change in cell state, from resting to activated. Moreover, the fate of neutrophils may also involve distinct differentiation programs yielding various subsets of pro or anti-tumor neutrophils. In this review, we will discuss the current knowledge on neutrophils heterogeneity across different tissues and their impact on tumorigenesis, as well as neutrophil-based therapeutic strategies that have shown promising results in pre-clinical studies, paving the way for the design of neutrophil-based next generation immunotherapy.

Background: Never-smokers and never-drinkers patients (NSND) suffering from oral squamous cell carcinoma (OSCC) are epidemiologically different from smokers drinkers (SD). We therefore hypothesized that they harbored distinct targetable molecular alterations. Patients and methods: Data from The Cancer Genome Atlas (TCGA) (discovery set), Gene Expression Omnibus and Centre Léon Bérard (CLB) (3 validation sets) with available gene expression profiles of HPV-negative OSCC from NSND and SD were mined. Protein expression profiles and genomic alterations were also analyzed from TCGA, and a functional pathway enrichment analysis was performed. Formalin-fixed paraffin-embedded (FFPE) samples from 44 OSCC including 20 NSND and 24 SD treated at CLB were retrospectively collected to perform targeted-sequencing of 2,559 transcripts (HTG EdgeSeq system), and CD3, CD4, CD8, IDO1 and PD-L1 expression analyses by immunohistochemistry (IHC). Enrichment of a six-gene interferon-γ signature of clinical response to pembrozulimab (PD-1 inhibitor) was evaluated in each sample from all cohorts, using the single sample gene set enrichment analysis method. Results: A total of 854 genes and 29 proteins were found to be differentially expressed between NSND and SD in TCGA. Functional pathway analysis highlighted an overall enrichment for immune-related pathways in OSCC from NSND, especially involving T-cell activation. Interferon-γ response and PD1 signaling were strongly enriched in NSND. IDO1 and PD-L1 were overexpressed and the score of response to pembrolizumab was higher in NSND compared to SD, although the mutational load was lower in NSND. IHC analyses in the CLB cohort evidenced IDO1 and PD-L1 overexpression in tumor cells that was associated with a higher rate of tumor-infiltrating T-cells in NSND compared to SD. Conclusion: The main biological and actionable difference between OSCC from NSND and SD lies in the immune microenvironment, suggesting a higher clinical benefit of PD-L1 and IDO1 inhibition in OSCC from NSND.

Beyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil‐platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. Using ImageStreamX (ISX) imaging flow cytometer, we were not only allowed able to detect CD15⁺ CD14⁻ CD36⁺ ITGA2B⁺ NPAs in both healthy donors' (HDs) and cancer patients' bloods, but we also showed that NPAs result from the binding of platelets preferentially to low‐density neutrophils (LDNs) as opposed to normal‐density neutrophils (NDNs). By reanalyzing two independent public scRNAseq data of whole blood leukocytes from cancer patients and HDs, we could identify a subset of neutrophils with high platelet gene expression that may correspond to NPAs. Moreover, we showed that cancer patients' derived NPAs possessed a distinct molecular signature compared to the other neutrophil subsets, independently of platelet genes. Gene ontology (GO) term enrichment analysis of this NPAs‐associated neutrophil transcriptomic signature revealed a significant enrichment of neutrophil degranulation, chemotaxis and trans‐endothelial migration GO terms. Lastly, using The Cancer Genome Atlas (TCGA), we could show by multivariate Cox analysis that the NPAs‐associated neutrophil transcriptomic signature was associated with a worse patient prognosis in several cancer types. These results suggest that neutrophils from NPAs are systemically primed by platelets empowering them with cancer progression capacities once at tumor site. NPAs may therefore hold clinical utility as novel noninvasive blood prognostic biomarker in cancer patients with solid tumors.

Prominent changes in the gut microbiota (referred to as “dysbiosis”) play a key role in the development of allergic disorders, but the underlying mechanisms remain unknown. Study of the delayed-type hypersensitivity (DTH) response in mice contributed to our knowledge of the pathophysiology of human allergic contact dermatitis. Here we report a negative regulatory role of the RIG-I–like receptor adaptor mitochondrial antiviral signaling (MAVS) on DTH by modulating gut bacterial ecology. Cohousing and fecal transplantation experiments revealed that the dysbiotic microbiota of Mavs^−/− mice conferred a proallergic phenotype that is communicable to wild-type mice. DTH sensitization coincided with increased intestinal permeability and bacterial translocation within lymphoid organs that enhanced DTH severity. Collectively, we unveiled an unexpected impact of RIG-I–like signaling on the gut microbiota with consequences on allergic skin disease outcome. Primarily, these data indicate that manipulating the gut microbiota may help in the development of therapeutic strategies for the treatment of human allergic skin pathologies. Significance Growing evidence suggests that prominent changes in the gut microbial communities (dysbiosis) play a key role in the development of allergic disorders, but the underlying mechanisms remain largely unknown. Here, we used a murine model of human allergic contact dermatitis to demonstrate a regulatory role of the adaptor mitochondrial antiviral signaling (MAVS) RIG-I–like receptors on disease outcome by modulating gut barrier function and bacterial ecology. Our results highlight an unexpected role of the RIG-I–MAVS pathway in maintenance of intestinal barrier function and modulation of gut commensal flora to prevent the development of inflammatory diseases such as allergy. These data provide a rationale for manipulating the gut microbiota as a therapeutic intervention in subjects at risk of developing allergy.

Although several tolerance induction protocols have been successfully implemented in adult renal transplantation, no tolerance induction approach has, as yet, been defined for solid-organ transplantations in young infants. Pediatric transplant recipients have a pressing demand for the elaboration of tolerance induction regimens. Indeed, since they display a longer survival time, they are exposed to a higher level of risks linked to long-term immunosuppression (IS) and to chronic rejection. Interestingly, central tolerance induction may be of great interest in newborns, because of their immunological immaturity and the important role of the thymus at this early stage in life. The present review aims to clarify mechanisms and strategies of tolerance induction in these immunologically premature recipients. We first introduce the discovery and mechanisms of neonatal tolerance in murine experimental models, and subsequently analyze tolerance induction in human newborn infants. Hematopoietic mixed chimerism in neonates is also discussed based on in utero hematopoietic stem cell (HSC) transplant studies. We then review the recent advances in tolerance induction approaches in adults, including the infusion of HSCs associated with less toxic conditioning regimens, regulatory T cells/facilitating cells/mesenchymal stem cells transplantation, costimulatory blockade, as well as thymus manipulation. Finally, IS withdrawal in pediatric solid organ transplant is discussed. In conclusion, the establishment of transplant tolerance induction in infants is promising and deserves further investigations. Future studies could focus on the selection of patients, on less toxic conditioning regimens, and on biomarkers for IS minimization or withdrawal.