High neutrophil counts and cancer progression involve a complex interaction between the immune system and tumor biology. Neutrophils are a type of white blood cell, and their elevated presence, known as neutrophilia, commonly indicates inflammation or infection. In the context of cancer, however, this high count suggests a systemic inflammatory state that influences the development and spread of the disease. Tumors can hijack the immune response, turning some immune cells into collaborators that promote tumor growth and metastasis. Tracking the levels of these cells has become a valuable area of research in oncology.
Understanding Neutrophils and Neutrophilia
Neutrophils are the most abundant type of white blood cell, typically making up 50% to 70% of the total white blood cell count in healthy adults. Produced in the bone marrow, they function as the immune system’s first responders, rapidly migrating to sites of injury or infection. Their role is to engulf and destroy invading microorganisms through phagocytosis, often by releasing enzymes and reactive oxygen species to neutralize threats.
An absolute neutrophil count typically ranges from 2,500 to 7,000 cells per microliter of blood in adults. Neutrophilia is defined as an absolute neutrophil count exceeding this normal range, usually considered above 7,700 cells per microliter. While bacterial infections are the most frequent cause, chronic inflammation, injury, and certain medications can also lead to an elevated count. Persistent neutrophilia, especially without an obvious infection, can serve as a warning sign of an underlying condition, including malignancy.
The Dual Role in Tumor Microenvironments
Within the tumor microenvironment (TME), neutrophils display plasticity, meaning they can change function in response to local signals, leading to a dual role in cancer progression. They are categorized into two main functional phenotypes: the anti-tumor N1 phenotype and the pro-tumor N2 phenotype. This phenotypic switch is influenced by cytokines and signaling molecules released by tumor cells and other immune cells in the surrounding tissue.
The N1 phenotype is associated with anti-cancer activity, promoting immune activation and direct cytotoxicity toward tumor cells. These neutrophils limit tumor growth by releasing pro-inflammatory molecules, such as tumor necrosis factor-alpha and specific chemokines. These molecules help recruit and activate other anti-cancer immune cells like T-cells. In contrast, the N2 phenotype is the subset associated with high neutrophil counts and is actively recruited by the tumor to support its growth.
The N2 neutrophils promote malignancy by engaging in several mechanisms. They facilitate the growth of new blood vessels (angiogenesis) by secreting pro-angiogenic factors like vascular endothelial growth factor (VEGF). This blood supply is necessary for the tumor to receive nutrients and oxygen, enabling expansion. N2 neutrophils also suppress the activity of other immune cells, such as cytotoxic T-cells, by releasing immunosuppressive cytokines like transforming growth factor-beta (TGF-\(\beta\)) and Interleukin-10 (IL-10).
Pro-tumor neutrophils also contribute to the spread of cancer, known as metastasis. They release matrix-degrading enzymes, such as matrix metalloproteinases (MMPs), which break down the extracellular matrix surrounding the tumor. This creates pathways for cancer cells to escape into the bloodstream. High neutrophil counts are also implicated in the formation of Neutrophil Extracellular Traps (NETs), web-like structures made of DNA and proteins that trap circulating tumor cells. Although NETs are an immune defense mechanism, in cancer they can protect trapped tumor cells from immune destruction and promote adhesion to distant organs, establishing metastatic niches.
Neutrophil Counts as Diagnostic and Prognostic Indicators
Clinicians use high neutrophil counts, especially when compared to other immune cells, to gain insight into a patient’s disease status and prognosis. The Neutrophil-to-Lymphocyte Ratio (NLR) is a simple, cost-effective biomarker derived from a standard complete blood count (CBC). The NLR is calculated by dividing the absolute neutrophil count by the absolute lymphocyte count, offering a snapshot of the balance between the pro-tumor inflammatory response and the anti-tumor immune response.
An elevated NLR is correlated with a poorer prognosis across many types of solid tumors, including pancreatic, colorectal, lung, and ovarian cancers. This ratio indicates a persistent, systemic inflammatory state fueling cancer progression. For instance, an NLR greater than a certain cutoff, often around 4 or 5, is associated with reduced overall survival, progression-free survival, and increased likelihood of recurrence.
The NLR’s predictive value reflects two opposing forces: high neutrophil numbers suggest a dominant pro-tumor inflammatory response, while low lymphocyte numbers indicate a weakened anti-tumor immune defense. This measurement helps guide treatment decisions, as an elevated NLR is sometimes linked to a reduced response to conventional therapies, such as chemotherapy. Because the NLR is readily available and inexpensive, it has become a widely utilized tool for risk stratification in oncology.
Therapeutic Strategies Targeting Neutrophils
The recognition of the pro-tumor role of N2 neutrophils has opened new avenues for cancer treatment focused on manipulating these cells. Current research explores two strategies: inhibiting the recruitment and function of pro-tumor neutrophils, and actively reprogramming the cells to an anti-tumor phenotype. The goal is to neutralize cancer-promoting effects without compromising the neutrophils’ ability to fight infections.
One approach involves blocking the signaling pathways that recruit neutrophils to the tumor site. Chemokine receptors, such as CXCR1 and CXCR2, are expressed on neutrophils and act as homing beacons in response to tumor-secreted signals. Inhibiting CXCR2, for example, is a strategy tested in clinical trials to prevent the accumulation of pro-tumor neutrophils. This has shown success in preclinical models of various cancers. Combining CXCR2 inhibitors with existing treatments like chemotherapy may enhance the effectiveness of traditional drugs.
The second strategy involves shifting the functional polarization of neutrophils from the N2 state back to the N1 state. This repolarization aims to convert the tumor’s allies into anti-cancer fighters. Researchers are investigating compounds that interfere with the signaling molecules responsible for N2 polarization, such as TGF-\(\beta\). The goal is restoring the neutrophils’ ability to directly kill cancer cells. Targeting neutrophil plasticity represents a sophisticated method for leveraging the body’s immune system to combat malignancy.