The Bilateral Interplay between Cancer Immunotherapies and Neutrophils’ Phenotypes and Sub-Populations

Abstract

Immunotherapy has become a leading modality for the treatment of cancer, but despite its increasing success, a substantial number of patients do not benefit from it. Cancer-related neutrophils have become, in recent years, a subject of growing interest. Distinct sub-populations of neutrophils have been identified at advanced stages of cancer. In this study, we aimed to evaluate the role of neutrophils in mediating the efficacy of immune checkpoint inhibitors (ICI) treatments (α-PD-1/PD-L1), by assessing lung tumor models in mice. We found that G-CSF overexpression by the tumor significantly potentiates the efficacy of ICI, whereas neutrophils’ depletion abrogated their responses. Adoptive transfer of circulating normal-density neutrophils (NDN) resulted in significantly reduced tumor growth, whereas low-density neutrophils (LDN) had no effect. We next investigated the effect of ICI on neutrophils’ functions. Following α-PD-L1 treatment, NDN displayed increased ROS production and increased cytotoxicity toward tumor cells but decreased degranulation. Together, our results suggest that neutrophils are important mediators of the ICI treatments and that mainly NDN are modulated following α-PD-L1 treatment. This research provides a better understanding of the function of neutrophils following immunotherapies and their impact on the efficacy of immunotherapy, supporting better understanding and future improvement of currently available treatments.

The Effects of GCSF Primary Prophylaxis on Survival Outcomes and Toxicity in Patients with Advanced Non-Small Cell Lung Cancer on First-Line Chemoimmunotherapy: A Sub-Analysis of the Spinnaker Study

“…PD-L1 expression has also been shown to be a marker for poor prognosis [ 18 , 19 ]. In addition to this, GCSF prophylaxis has been suggested as a potential adjunct to immunotherapy [ 7 ]. Despite these reports, these numerous factors were shown not to influence GCSF primary prophylaxis use in this analysis.…”

“…Further work, including experimental models, needs to be undertaken to assess the dynamics and characterisation of the peripheral and tumour-infiltrating immune cells and changes in the NLR following GCSF administration and the nature and duration of these changes, taking into account that patients tend to be on relatively short courses of GCSF prophylaxis of 5–7 days. While GCSF has been reported to increase PD-L1 expression on neutrophils and contribute to increased tumour shrinkage in cancers with GCSF expression, further research on the effects of GCSF prophylaxis on these and the duration of these effects is required [ 7 ].…”

“…There have been reports of GCSF increasing peripheral neutrophil recruitment and programmed death-ligand 1 (PD-L1) expression on neutrophils, as well as a greater decrease in tumour volume in cancers with higher GCSF expression. These mechanisms could result in increased efficacy of immune checkpoint inhibitors (ICIs); therefore, GCSF has been put forward as a potential adjuvant therapy to ICIs [ 7 ].…”

Circulating low density neutrophils are associated with resistance to anti‐PD1 immunotherapy in squamous head and neck cancer

“…18 However distinct sub-populations of neutrophils can be able to display both anti-and pro-tumor effects. 9, 18 Zuazo and colleagues studied patients with lung cancer treated with second-line ICI monotherapy and found a strong enrichment of LDNs in those cases considered as progressors, while this cellular population was virtually absent in those individuals considered as responders. 19 The same group validated these findings in a cohort of patients with advanced non-small cell lung cancer treated with ICIs as first-line therapy.…”

Diverse Neutrophil Functions in Cancer and Promising Neutrophil-Based Cancer Therapies

“…To avoid confusion, since the term HDN does not refer to a specific neutrophil subpopulation except neutrophils with unaltered normal density, normal-density neutrophils (NDNs) seems to be a more suitable term [ 75 ], and thus we use it in this review. It should be noted that TANs can come from both NDNs and LDNs [ 42 ], but because LDNs are more likely to have a pro-tumor phenotype [ 76 ], we hypothesized that N1 TANs come from the NDN fraction and N2 TANs come from the LDN fraction after entering the tumor microenvironment from the bloodstream.…”