Effect of neutrophils on tumor immunity and immunotherapy resistance with underlying mechanisms

Abstract

Neutrophils are key mediators of the immune response and play essential roles in the development of tumors and immune evasion. Emerging studies indicate that neutrophils also play a critical role in the immunotherapy resistance in cancer. In this review, firstly, we summarize the novel classification and phenotypes of neutrophils and describe the regulatory relationships between neutrophils and tumor metabolism, flora microecology, neuroendocrine and tumor therapy from a new perspective. Secondly, we review the mechanisms by which neutrophils affect drug resistance in tumor immunotherapy from the aspects of the immune microenvironment, tumor antigens, and epigenetics. Finally, we propose several promising strategies for overcoming tumor immunotherapy resistance by targeting neutrophils and provide new research ideas in this area.

Keywords: Tumor microenvironment; immune resistance; immunotherapy; neutrophil; tumor.

FIGURE 1

Interactions between neutrophils and other immune cells. Neutrophils can affect the proliferation and activity of B cells through BAFF and other mediators. IL‐12 and other cytokines promote the differentiation of monocytes into macrophages and enhance their antibacterial activity. There is bidirectional regulation between neutrophils and T cells, and neutrophils can affect the activation, differentiation and proliferation of T cells. As for dendritic cells, neutrophils can not only directly affect their recruitment, activation and maturation, but also influence T cells and NK cells with dendritic cells as bridges. In addition, neutrophils can also directly affect the killing activity of NK cells and the production of cytokines through IL‐18. Abbreviations: NK, natural killer; TNF, tumor necrosis factor; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; BAFF, B cell activating factor; APRIL, a proliferation‐inducing ligand.

FIGURE 2

Novel progress has been made in the research on the regulation of tumor‐associated neutrophils. (A) The tumor metabolism and certain intermediate metabolites regulate the secretion of crucial downstream molecules or cytokines through multiple signaling pathways, thereby influencing the infiltration, polarization, and expression of immunosuppressive signals in neutrophils. (B) The microbial ecology within tumors can directly induce neutrophils to secrete NE or form NETs, as well as cause changes in neutrophil phenotype. Furthermore, it can recruit neutrophils and enhance NETs formation through the secretion of inflammatory factors or via TLR4‐ROS signal transduction. (C) The release of various neuroendocrine hormones, including adrenaline, noradrenaline, serotonin, ach, and cortisol, can impair the phagocytic and clearance abilities of neutrophils, while also facilitating the recruitment and activation of neutrophils. (D) Tumor treatment, either independently or through the induction of chemotactic factor release, can impact the quantity, phenotype, and NETs formation of neutrophils. Moreover, certain therapies can induce the recruitment and chemotaxis of neutrophils by affecting the immunogenic cell death of tumor cells, leading to the release of chemotactic factors. Abbreviations: NE, neutrophil elastase; NETs, neutrophil extracellular traps; TLR4, Toll‐like receptor 4; ROS, Reactive oxygen species; mtDNA, mitochondrial DNA; HBV, Hepatitis B virus; Fn, Fusobacterium nucleatum; S. aureus, Staphylococcus aureus; P. aeruginosa, Pseudomonas aeruginosa; P. gingivalis, Porphyromonas gingivalis; C. jejuni, Campylobacter jejuni; HPA, hypothalamus‐pituitary‐adrenal; Ach, acetylcholine; RT, radiotherapy; OV, oncolytic virus; BCG, bacillus Calmette‐Guerin; ICD, immunogenic cell death.

FIGURE 3

Mechanisms of neutrophil‐mediated tumor immunotherapy resistance. From the aspect of promoting the formation of immunosuppressive microenvironment, neutrophils mainly inhibit the activation and proliferation of immune cells through some cytokines and signaling pathways, and promote their injury, apoptosis or transformation to immunosuppressive phenotype. From the aspect of affecting tumor antigens, neutrophils can damage tumor cell DNA by producing ROS, resulting in tumor antigen loss or mutation. In addition, neutrophils can also affect the expression of epigenetic molecules in tumor cells through exosomes, and promote the immune escape of tumors. Abbreviations: ROS, reactive oxygen species; iNOS, inducible nitric oxide synthase; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor, NETs, neutrophil extracellular traps; NK, natural killer; MDSC, myeloid‐derived suppressor cell; EMT, epithelial‐mesenchymal transition; OSM, oncostatin‐M; ARG1, arginase‐1; WTAP, wilms' tumor 1‐associating protein; m6A, N6‐methyladenosine; THBS1, thrombospondin‐1; TAN, tumor associated neutrophil; TNF, tumor necrosis factor; STAT3, signal transducer and activator of transcription 3; FOXP3, forkhead box protein 3.

FIGURE 4

Strategies for overcoming tumor immunotherapy resistance by targeting neutrophils. Activation and recruitment of neutrophils can be inhibited by using related receptor inhibitors or blocking some signaling pathways, thus blocking subsequent reactions caused by neutrophils. From the perspective of targeting neutrophil derivatives, modifying neutrophil derived exosomes with specific ligands can activate surrounding immune cells to stimulate an immune response. In addition, the expression of PD‐1 on T cell surface can be inhibited by targeting glycometabolites and lipid metabolism‐related proteins of neutrophils. Reprogramming neutrophils by regulating their genes is also a strategy. For example, the elimination of IRAK‐M and Tollip can inhibit PD‐L1 expression. Promoting SETD2 expression can inhibit the production of chemokines and colony‐stimulating factors. Upregulation of CD80, CD86, and MHC II can reprogram neutrophils into atypical antigen‐presenting cells. Blocking the immune checkpoint of neutrophils with blockers can effectively enhance the antitumor immune responses. From the perspective of targeting NETs, on one hand, NETs formation can be inhibited by inhibiting proteins related to NETs formation, on the other hand, NETs can also be dissolved by DNA enzymes. Abbreviations: NDE, neutrophil‐derived exosome; NETs, neutrophil extracellular traps; NK, natural killer; MDSC, myeloid‐derived suppressor cell; TLR, Toll‐like receptor; IRAK‐M, interleukin‐1 receptor‐associated kinase M; VISTA, T‐cell‐activated immunoglobulin inhibitor of structural domain V; LILRB2, leukocyte immunoglobulin‐like receptor subfamily B member 2; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain; MPO, myeloperoxidase; NE, neutrophil elastase; PAD4, protein arginine deaminase type 4; SETD2, SET domain containing 2; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor, TGF, transforming growth factor; Wip1, wild‐type p53 induced phosphatase 1.