CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors

Simoncello, Francesca; Piperno, Giulia Maria; Caronni, Nicoletta; Amadio, Roberto; Cappelletto, Ambra; Canarutto, Giulia; Piazza, Silvano; Bicciato, Silvio; Benvenuti, Federica

doi:10.1080/2162402x.2022.2059876

Cited by 27 publications

(18 citation statements)

References 71 publications

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“…Previous studies have demonstrated an important role for a proinflammatory tumor microenvironment in KP LUAD development, with dendritic cells (Maier et al, 2020), macrophages (Cortez-Retamozo et al, 2012), neutrophils (Ancey et al, 2021; Engblom et al, 2017; Faget et al, 2017; Simoncello et al, 2022), and T cells (Horton et al, 2021; Jin et al, 2019a) all implicated in the etiology of this animal model. Considering the overlap of these cell types with those involved in bacterial response, we hypothesized that dysbiosis may accelerate tumor growth by altering the immune microenvironment.…”

Section: Resultsmentioning

confidence: 74%

Acidovorax temperanspolarizes T17 cells and skews neutrophil maturation to promote lung adenocarcinoma development

Stone

Muhlinen

Zhang

et al. 2022

Preprint

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Dysbiosis, or changes within the microbiome, is a common feature of solid tumors, however whether this dysbiosis directly contributes to tumor development is largely unknown. We previously characterized the lung cancer microbiome and identified Acidovorax temperans as enriched in tumors. In this study, we instilled A. temperans in an animal model driven by mutant Kras and Tp53 alleles. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic genotype with increased cytokine signaling, with a global shift away from IL-1β signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells which polarized to an IL-17A+ phenotype detectable in CD4+ and γδ populations. T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate dysbiosis promotes tumor growth by modulating inflammation.

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Section: Resultsmentioning

confidence: 74%

Acidovorax temperanspolarizes T17 cells and skews neutrophil maturation to promote lung adenocarcinoma development

Stone

Muhlinen

Zhang

et al. 2022

Preprint

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“…Previous studies showed that there is a negative correlation between CXCL-5 mediated mature neutrophil density and CD8+ T cells in lung tumor nodules. Moreover, neutrophils accumulating in lung tissue contribute to inhibit effector functions in CD8+ T cells (104). Taken together, the complex interaction of TANs with T cells in lung cancer remains complex.…”

Section: Tumor-associated Neutrophilsmentioning

confidence: 99%

T lymphocyte cell: A pivotal player in lung cancer

Yuan

Wang

et al. 2023

Front. Immunol.

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Lung cancer is responsible for the leading cause of cancer-related death worldwide, which lacks effective therapies. In recent years, accumulating evidence on the understanding of the antitumor activity of the immune system has demonstrated that immunotherapy is one of the powerful alternatives in lung cancer therapy. T cells are the core of cellular immunotherapy, which are critical for tumorigenesis and the treatment of lung cancer. Based on the different expressions of surface molecules and functional points, T cells can be subdivided into regulatory T cells, T helper cells, cytotoxic T lymphocytes, and other unconventional T cells, including γδ T cells, nature killer T cells and mucosal-associated invariant T cells. Advances in our understanding of T cells’ functional mechanism will lead to a number of clinical trials on the discovery and development of new treatment strategies. Thus, we summarize the biological functions and regulations of T cells on tumorigenesis, progression, metastasis, and prognosis in lung cancer. Furthermore, we discuss the current advancements of technologies and potentials of T-cell-oriented therapeutic targets for lung cancer.

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“…In both bulk- and scRNA-seq, we observed the unique distribution pattern of neutrophils, which indicated a potential correlation between neutrophils and necroptosis. According to previous studies, neutrophils were tightly associated with the progression of various tumors including lung cancer ( 55 , 56 ). In particular, TANs were polarized into 2 subtypes (N1 and N2) based on a variety of environmental factors including cytokines and chemokines in the TME, and the N1 TANs exhibited tumor suppression via activation of CD8+ T cells, while the N2 neutrophils stimulated tumor growth, invasion, metastasis, and angiogenesis ( 57 ).…”

Section: Discussionmentioning

confidence: 94%

Necroptosis-related lncRNAs: Combination of bulk and single-cell sequencing reveals immune landscape alteration and a novel prognosis stratification approach in lung adenocarcinoma

Yao

Zuo

et al. 2022

Front. Oncol.

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Necroptosis, which is recently recognized as a form of programmed cell death, plays a critical role in cancer biology, including tumorigenesis and cancer immunology. It was recognized not only to defend against tumor progression by suppressing adaptive immune responses but also to promote tumorigenesis and cancer metastasis after recruiting inflammatory responses. Thus the crucial role of necrosis in tumorigenesis has attracted increasing attention. Due to the heterogeneity of the tumor immune microenvironment (TIME) in lung adenocarcinoma (LUAD), the prognosis and the response to immunotherapy vary distinctly across patients, underscoring the need for a stratification algorithm for clinical practice. Although previous studies have formulated the crucial role of lncRNAs in tumorigenicity, the relationship between necroptosis-related lncRNAs, TIME, and the prognosis of patients with LUAD was still elusive. In the current study, a robust and novel prognostic stratification model based on Necroptosis-related LncRNA Risk Scoring (NecroLRS) and clinicopathological parameters was constructed and systemically validated in both internal and external validation cohorts. The expression profile of four key lncRNAs was further validated by qRT-PCR in 4 human LUAD cell lines. And a novel immune landscape alteration was observed between NecroLRS-High and -Low patients. To further elucidate the mechanism of necroptosis in the prognosis of LUAD from a single-cell perspective, a novel stratification algorithm based on K-means clustering was introduced to extract both malignant and NecroLRS-High subsets from epithelial cells. And the necroptosis-related immune infiltration landscape and developmental trajectory were investigated respectively. Critically, NecroLRS was found to be positively correlated with neutrophil enrichment, inflammatory immune response, and malignant phenotypes of LUAD. In addition, novel ligand-receptor pairs between NecroLRS-High cells and other immunocytes were investigated and optimal therapeutic compounds were screened to provide potential targets for future studies. Taken together, our findings reveal emerging mechanisms of necroptosis-induced immune microenvironment alteration on the deteriorative prognosis and may contribute to improved prognosis and individualized precision therapy for patients with LUAD.

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CXCL5-mediated accumulation of mature neutrophils in lung cancer tissues impairs the differentiation program of anticancer CD8 T cells and limits the efficacy of checkpoint inhibitors

Cited by 27 publications

References 71 publications

Acidovorax temperanspolarizes T17 cells and skews neutrophil maturation to promote lung adenocarcinoma development

Acidovorax temperanspolarizes T17 cells and skews neutrophil maturation to promote lung adenocarcinoma development

T lymphocyte cell: A pivotal player in lung cancer

Necroptosis-related lncRNAs: Combination of bulk and single-cell sequencing reveals immune landscape alteration and a novel prognosis stratification approach in lung adenocarcinoma

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