Exploiting knowledge of neutrophil protumour and antitumour phenotypes to treat cancer

The crosstalk between neutrophils and cancer is complex (Nat Rev Immunol. 2022;22:173–187). Together with macrophages, neutrophils are the body’s main immunosuppressive cells in the context of cancer but are its first line of defence in the context of infections. In the early days of research in this area, it was recognised that neutrophils emerged from bone marrow into blood with a very restricted number of functions and it was assumed that they maintained this state. We now know that there is considerable neutrophil plasticity and that these cells can adopt antitumour or protumour phenotypes, depending on their environment. Tumours of the same type can have different tumour microenvironments (TME) and neutrophils present at a different state.

The first of two key knowledge gaps involves identifying the trigger within the TME that makes neutrophils switch between phenotypes. Understanding this is crucial to finding ways to at least suppress their protumorigenic activity, and ideally trigger their antitumorigenic activity. With my research group, we recently demonstrated that in a murine model of acute radiation injury to the lung, when neutrophils infiltrate injured lung tissue from the blood, they are rapidly activated to assist in the regeneration of damaged tissue, but this also leads to them becoming key drivers of a protumorigenic TME (Nat Cancer. 2022;3:173–187). While the lifespan of neutrophils within tissue is short, their constant supply from the blood ensures adequate levels to maintain a constant effect. The second area of neutrophil research that requires clarification concerns the initial priming of neutrophils already in the circulation, the mechanisms of which have consequences for the way they then polarise within the primary tumour.

The role of neutrophils in tumour growth and development suggests a number of clinical applications. There is the potential to use them as a prognostic indicator in some cancers, exploiting the priming situation and early phenotypic changes seen in circulating neutrophils. This would rely on identification of a very specific neutrophil marker. While it is unlikely that such a marker could be used on its own to determine prognosis, it could be useful in combination with other clinical and disease factors. If validated, specific neutrophil markers may be easily detected in the clinic using a simple, non-invasively obtained blood sample.

Targeting neutrophils for therapeutic benefit is another key opportunity. However, given their importance in the body’s defence mechanisms, we need to understand their complex network of interactions and what they do in promoting tumours to be able to anticipate the variety of effects that may result from blocking one specific function. It will not be possible to avoid some negative effects following interruption of neutrophil activity – after all, neutropenia can be a life-threatening condition – but it seems reasonable to suggest that neutrophils could be blocked over limited and well-defined periods of time, possibly with additional supportive therapy, as required.

The fact that neutrophils are part of a highly complex network, interacting with and influencing the activity of all different types of cells within the TME, makes working with them particularly challenging. I am hopeful that it will not take too long before the considerable efforts of investigators in this growing area are translated into valuable clinical applications.