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.
Highlights
Immunotherapy and immune modulation have become central to leading efforts in the research and practice of cancer treatment
We aimed to evaluate the bilateral effects of α-PD-L1/PD-1 immunotherapies and neutrophils‘ phenotypes and sub-populations in murine lung tumor models, with emphasis on the role of G-CSF and the differential effects of immune checkpoint inhibitors (ICI) on the different neutrophils’ subpopulations
We aimed to assess the impact of G-CSF on tumor growth in the LLC model and appraise whether the presence of G-CSF could modify the efficacy of immune checkpoint blockade in this model
Summary
Immunotherapy and immune modulation have become central to leading efforts in the research and practice of cancer treatment. It has been shown that the presence of neutrophils in the circulation and in the tumor is associated with poor prognosis in many types of cancer [8,9] and affects various aspects of cancer biology [3,10]. Normal-density neutrophils (NDN) can be found in the circulation of both healthy donors and cancer patients, while low-density neutrophils (LDN) can be found mostly in chronic inflammation and cancer [16,17]. The amount and presence of LDN in mice and humans significantly increases with tumor growth. NDN are more prone to present anti-tumor properties, whereas LDN are more prone to present a pro-tumor phenotype
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