SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

Owing to their tremendous diversity and plasticity, immune cells exert multifaceted functions in tumor-bearing hosts, ranging from anti-tumor to pro-tumor activities. Tumor immune landscapes differ greatly between and within cancer types. Emerging evidence suggests that genetic aberrations in cancer cells dictate the immune contexture of tumors. Here, we review the current understanding of the mechanisms whereby common drivers of tumorigenesis modulate the tumor immune milieu. We discuss these findings in the context of clinical observations and examine how cancer-cell-intrinsic properties can be exploited to maximize the benefit of immunomodulatory therapies. Understanding the relationship between cancer cell-intrinsic genetic events and the immune response may enable personalized immune intervention strategies for cancer patients.

Cancer-associated systemic inflammation is strongly linked with poor disease outcome in cancer patients 1,2. For most human epithelial tumour types, high systemic neutrophil-tolymphocyte ratios are associated with poor overall survival 3 , and experimental studies have demonstrated a causal relationship between neutrophils and metastasis 4,5. However, the cancer cell-intrinsic mechanisms dictating the substantial heterogeneity in systemic neutrophilic inflammation between tumour-bearing hosts are largely unresolved. Using a panel of 16 distinct genetically engineered mouse models (GEMMs) for breast cancer, we have uncovered a novel role for cancer cell-intrinsic p53 as a key regulator of pro-metastatic neutrophils. Mechanistically, p53 loss in cancer cells induced secretion of Wnt ligands that stimulate IL-1β production by tumour-associated macrophages, which drives systemic inflammation. Pharmacological and genetic blockade of Wnt secretion in p53-null cancer cells reverses IL-1β expression by macrophages and subsequent neutrophilic inflammation, resulting in reduced metastasis formation. Collectively, we demonstrate a novel mechanistic link between loss of p53 in cancer cells, Wnt ligand secretion and systemic neutrophilia that potentiates metastatic progression. These insights illustrate the importance of the genetic makeup of breast tumours in dictating pro-metastatic systemic inflammation, and set the stage for personalized immune intervention strategies for cancer patients. 4 Main text To determine how pro-metastatic systemic inflammation is influenced by genetic aberrations in tumours, we studied 16 GEMMs for breast cancer carrying different tissue-specific mutations. These GEMMs represent most subtypes of human breast cancer, including ductal and lobular carcinoma, oestrogen receptor-positive (luminal A), HER2 + , triple-negative and basal-like breast cancer. Because we and others have demonstrated that neutrophils expand systemically and promote metastasis 5-10 , we evaluated circulating neutrophil levels as a marker for systemic inflammation in mammary tumour-bearing mice with end-stage disease. As expected, most tumour-bearing mice displayed an increase in circulating neutrophils as compared to non-tumour-bearing animals (wild-type [WT]) (Fig. 1a). Like the inter-patient heterogeneity in systemic inflammation in human breast cancer 11 , we observed a striking variability in the extent of neutrophilia between the different tumour-bearing GEMMs (Fig. 1a, Extended Data Fig. 1a). We found that the models exhibiting high neutrophil expansion displayed a subset of neutrophils expressing the stem cell marker cKIT (Fig. 1b), indicative of an immature neutrophil phenotype 5. We subsequently searched for commonalities and differences among the 16 GEMMs with regards to high versus low systemic neutrophil levels. Strikingly, mice bearing tumours with a p53 deletion exhibited the most pronounced circulating neutrophil levels (Fig. 1a). The difference in magnitude of systemic inflammation between p53proficient and p...