The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

Sun, Yueqin; Yang, Qi; Shen, Jie; Wei, Ting; Shen, Weitao; Zhang, Nan; Luo, Peng; Zhang, Jian

doi:10.3389/fcell.2021.745859

Cited by 22 publications

(14 citation statements)

References 49 publications

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“…On the other hand, non-smokers seemed to display a more immunosuppressed state, with a higher infiltration of M2 pro-tumor macrophages. Our findings are in agreement with a recent study that showed that NSCLC patients who are previous or current smokers had a higher TMB and neoantigen load, accompanied by a higher infiltration of immune cells, compared to those classified as never-smokers [ 70 ]. However, unlike previous studies similar to ours, using statistical models like Random Forest and Multiple Linear Regression, we report for the first time that these results are not affected by, and are not a sole artifact of, other confounding factors; at least for the dataset that we analyze in the present study.…”

Section: Discussionsupporting

confidence: 93%

“…However, unlike previous studies similar to ours, using statistical models like Random Forest and Multiple Linear Regression, we report for the first time that these results are not affected by, and are not a sole artifact of, other confounding factors; at least for the dataset that we analyze in the present study. Moreover, in accordance with our results, they also reported following mass cytometry (CyTOF) analysis of fresh NSCLC tissues, that smokers have a more immune-activated TME, while the TME of non-smokers is in an immunosuppressed or resting state [ 70 ]. Our findings further suggest a more complex relationship between smoking status and immune infiltration.…”

Section: Discussionsupporting

confidence: 90%

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Genomic Analysis of Waterpipe Smoke-Induced Lung Tumor Autophagy and Plasticity

Zaarour

Sharda

Azakir

et al. 2022

IJMS

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The role of autophagy in lung cancer cells exposed to waterpipe smoke (WPS) is not known. Because of the important role of autophagy in tumor resistance and progression, we investigated its relationship with WP smoking. We first showed that WPS activated autophagy, as reflected by LC3 processing, in lung cancer cell lines. The autophagy response in smokers with lung adenocarcinoma, as compared to non-smokers with lung adenocarcinoma, was investigated further using the TCGA lung adenocarcinoma bulk RNA-seq dataset with the available patient metadata on smoking status. The results, based on a machine learning classification model using Random Forest, indicate that smokers have an increase in autophagy-activating genes. Comparative analysis of lung adenocarcinoma molecular signatures in affected patients with a long-term active exposure to smoke compared to non-smoker patients indicates a higher tumor mutational burden, a higher CD8+ T-cell level and a lower dysfunction level in smokers. While the expression of the checkpoint genes tested—PD-1, PD-L1, PD-L2 and CTLA-4—remains unchanged between smokers and non-smokers, B7-1, B7-2, IDO1 and CD200R1 were found to be higher in non-smokers than smokers. Because multiple factors in the tumor microenvironment dictate the success of immunotherapy, in addition to the expression of immune checkpoint genes, our analysis explains why patients who are smokers with lung adenocarcinoma respond better to immunotherapy, even though there are no relative differences in immune checkpoint genes in the two groups. Therefore, targeting autophagy in lung adenocarcinoma patients, in combination with checkpoint inhibitor-targeted therapies or chemotherapy, should be considered in smoker patients with lung adenocarcinoma.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

Genomic Analysis of Waterpipe Smoke-Induced Lung Tumor Autophagy and Plasticity

Zaarour

Sharda

Azakir

et al. 2022

IJMS

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“…Cigarette smoking was found to impact both innate and adaptive immunity and affect gut microbiota composition [120,121]. Furthermore, several studies on NSCLC patients demonstrated improved clinical outcomes to the ICI therapy in smokers versus non-smokers, suggesting that smoking may contribute to higher immunogenicity and activation of the immune microenvironment [122,123]. To our knowledge, a similar analysis investigating the impact of smoking on ICI efficacy in melanoma patients has not been performed yet.…”

Section: Discussionmentioning

confidence: 99%

A Clinical Outcome of the anti-PD-1 Therapy of Melanoma in Polish Patients Is Mediated by Population-Specific Gut Microbiome Composition

Pietrzak¹,

Tomela²,

Olejnik-Schmidt³

et al. 2022

Preprint

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Gut microbiota is considered a key player modulating the efficacy of immune checkpoint inhibitor therapy. The study investigated the association between response to the anti-PD-1 therapy and the baseline gut microbiome in the Polish cohort of melanoma patients, alongside selected agents modifying the microbiome. Sixty-four melanoma patients enrolled for the anti-PD-1 therapy and 10 healthy subjects were recruited. Response to the treatment was assessed according to the response evaluation criteria in solid tumors, and patients were classified as responders or non-responders. The association between selected extrinsic factors and response was investigated using questionnaire-based analysis, and metataxonomics of the microbiota. The Bacteroidota to Firmicutes ratio was higher, and the richness was decreased in the responders. The abundance of Prevotella copri and Bacteroides uniformis was related to the response, whereas non-responder gut microbiota was enriched with Faecalibacterium prausnitzii and Desulfovibrio intestinalis, and some unclassified Firmicutes. Dietary patterns, including plant, dairy, and fat consumption, but also gastrointestinal tract functioning were significantly associated with the therapeutic effects of the therapy. The specific gut microbiota alongside diet were found associated with response to the therapy in the Polish population of melanoma patients.

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“…In contrast, the immune microenvironment of tumor from the non-smoking group is enriched for immunosuppressive related cells, including regulatory T cells and M2 macrophages. Finally, the non-smoking group also contained higher fractions of CD45RAhigh CD4+ T cells and CD45RAhigh CD8+ T cells, typically characteristic of naïve T cell subpopulations ( 54 ).…”

Section: Immune Landscape In Never-smoker Lung Cancer Patientsmentioning

confidence: 99%

Lung cancer in never smokers: Tumor immunology and challenges for immunotherapy

et al. 2022

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Lung cancer is the second most common and the most lethal malignancy worldwide. It is estimated that lung cancer in never smokers (LCINS) accounts for 10-25% of cases, and its incidence is increasing according to recent data, although the reasons remain unclear. If considered alone, LCINS is the 7th most common cause of cancer death. These tumors occur more commonly in younger patients and females. LCINS tend to have a better prognosis, possibly due to a higher chance of bearing an actionable driver mutation, making them amenable to targeted therapy. Notwithstanding, these tumors respond poorly to immune checkpoint inhibitors (ICI). There are several putative explanations for the poor response to immunotherapy: low immunogenicity due to low tumor mutation burden and hence low MANA (mutation-associated neo-antigen) load, constitutive PD-L1 expression in response to driver mutated protein signaling, high expression of immunosuppressive factors by tumors cells (like CD39 and TGF-beta), non-permissive immune TME (tumor microenvironment), abnormal metabolism of amino acids and glucose, and impaired TLS (Tertiary Lymphoid Structures) organization. Finally, there is an increasing concern of offering ICI as first line therapy to these patients owing to several reports of severe toxicity when TKIs (tyrosine kinase inhibitors) are administered sequentially after ICI. Understanding the biology behind the immune response against these tumors is crucial to the development of better therapeutic strategies.

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The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

Cited by 22 publications

References 49 publications

Genomic Analysis of Waterpipe Smoke-Induced Lung Tumor Autophagy and Plasticity

Genomic Analysis of Waterpipe Smoke-Induced Lung Tumor Autophagy and Plasticity

A Clinical Outcome of the anti-PD-1 Therapy of Melanoma in Polish Patients Is Mediated by Population-Specific Gut Microbiome Composition

Lung cancer in never smokers: Tumor immunology and challenges for immunotherapy

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