Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non‐small cell lung cancer

Sun, Li-Yue; Cen, Wen-Jian; Tang, Wenting; Long, Ya-Kang; Yang, Xinhua; Ji, Xiaomeng; Yang, Jushun; Zhang, Ren-Jing; Wang, Fang; Shao, Jian Yong; Du, Ziwei

doi:10.1002/cam4.4197

Cited by 11 publications

(9 citation statements)

References 30 publications

(37 reference statements)

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“…Multiple studies have confirmed that in patients with lung cancer undergoing systemic immune checkpoint inhibitor (ICI) therapy, those who smoke have an increased survival and better response rate to ICI compared with nonsmokers. Proposed mechanisms include increased programmed cell death ligand 1 expression and increased tumor mutational burden in non–small cell lung tumors of smokers . In patients with melanoma, the reports of smoking and response to ICI are limited.…”

Section: Discussionmentioning

confidence: 99%

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Jackson,

Jones,

Fluke

et al. 2024

JAMA Netw Open

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ImportanceWhile smoking is associated with a decreased incidence of cutaneous melanoma, the association of smoking with melanoma progression and death is not well defined.ObjectiveTo determine the association of smoking with survival in patients with early-stage primary cutaneous melanoma.Design, Setting, and ParticipantsThis cohort study performed a post hoc analysis of data derived from the randomized, multinational first and second Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLT-II). Participants were accrued for MSLT-I from January 20, 1994, to March 29, 2002; MSLT-II, from December 21, 2004, to March 31, 2014. Median follow-up was 110.0 (IQR, 53.4-120.0) months for MSLT-I and 67.6 (IQR, 25.8-110.2) months for MSLT-II. Patients aged 18 to 75 years with clinical stages I or II melanoma with a Breslow thickness of 1.00 mm or greater or Clark level IV to V and available standard prognostic and smoking data were included. Analyses were performed from October 4, 2022, to March 31, 2023.ExposureCurrent, former, and never smoking.Main Outcomes and MeasuresMelanoma-specific survival of patients with current, former, and never smoking status was assessed for the entire cohort and for nodal observation and among subgroups with sentinel lymph node biopsy (SLNB)–negative and SLNB-positive findings.ResultsOf 6279 included patients, 3635 (57.9%) were men, and mean (SD) age was 52.7 (13.4) years. The most common tumor location was an extremity (2743 [43.7%]), and mean (SD) Breslow thickness was 2.44 (2.06) mm. Smoking status included 1077 (17.2%) current, 1694 (27.0%) former, and 3508 (55.9%) never. Median follow-up was 78.4 (IQR, 30.5-119.6) months. Current smoking was associated with male sex, younger age, trunk site, thicker tumors, tumor ulceration, and SLNB positivity. Current smoking was associated with a greater risk of melanoma-associated death by multivariable analysis for the entire study (hazard ratio [HR], 1.48 [95% CI, 1.26-1.75]; P &lt; .001). Former smoking was not. The increased risk of melanoma-specific mortality associated with current smoking was greatest for patients with SLNB-negative melanoma (HR, 1.85 [95% CI, 1.35-2.52]; P &lt; .001), but also present for patients with SLNB-positive melanoma (HR, 1.29 [95% CI, 1.04-1.59]; P = .02) and nodal observation (HR, 1.68 [95% CI, 1.09-2.61]; P = .02). Smoking at least 20 cigarettes/d doubled the risk of death due to melanoma for patients with SLNB-negative disease (HR, 2.06 [95% CI, 1.36-3.13]; P &lt; .001).Conclusions and RelevanceThe findings of this cohort study suggest that patients with clinical stage I and II melanoma who smoked had a significantly increased risk of death due to melanoma. Smoking status should be assessed at time of melanoma diagnosis and may be considered a risk factor for disease progression.

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Section: Discussionmentioning

confidence: 99%

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Jackson,

Jones,

Fluke

et al. 2024

JAMA Netw Open

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“…Accordingly, the chronic inflammation of the pulmonary system because of cigarette smoking has been thought to be associated with an immunosuppressive tumor microenvironment in LUAD 28 . In comparison with nonsmoker patients, an increased mutational burden was shown to enhance the sensitivity to immune checkpoint inhibitors in NSCLC patients with smoking history 29 . A higher mutational burden has been correlated with a favorable response in NSCLC patients who received anti‐PD‐1 therapy 30 .…”

Section: Discussionmentioning

confidence: 99%

“…28 In comparison with nonsmoker patients, an increased mutational burden was shown to enhance the sensitivity to immune checkpoint inhibitors in NSCLC patients with smoking history. 29 A higher mutational burden has been correlated with a favorable response in NSCLC patients who received anti-PD-1 therapy. 30 In this study, AIM2 upregulation is dominant for LUAD derived from The intracellular inflammatory responses have been highly correlated with the metastatic progression in many types of cancer.…”

Section: Aim2 Upregulation Potentiates the Expression Of Pd-l1 In Smo...mentioning

confidence: 99%

AIM2 upregulation promotes metastatic progression and PD‐L1 expression in lung adenocarcinoma

et al. 2022

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Cancer metastasis leading to the dysfunction of invaded organs is the main cause of the reduced survival rates in lung cancer patients. However, the molecular mechanism for lung cancer metastasis remains unclear. Recently, the increased activity of inflammasome appeared to correlate with the metastatic progression and immunosuppressive ability of various cancer types. Our results showed that the mRNA levels of absence in melanoma 2 (AIM2), one of the inflammasome members, are extensively upregulated in primary tumors compared with normal tissues derived from the TCGA lung adenocarcinoma (LUAD) database. Moreover, Kaplan‐Meier analysis demonstrated that a higher mRNA level of AIM2 refers to a poor prognosis in LUAD patients. Particularly, AIM2 upregulation is closely correlated with smoking history and the absence of EGFR/KRAS/ALK mutations in LUAD. We further showed that the endogenous mRNA levels of AIM2 are causally associated with the metastatic potentials of the tested LUAD cell lines. AIM2 knockdown suppressed but overexpression promoted the migration ability and lung colony–forming ability of tested LUAD cells. In addition, we found that AIM2 upregulation is closely associated with an increased level of immune checkpoint gene set, as well as programmed cell death‐ligand 1 (PD‐L1) transcript, in TCGA LUAD samples. AIM2 knockdown predominantly repressed but overexpression enhanced PD‐L1 expression via altering the activity of PD‐L1 transcriptional regulators NF‐κB/STAT1 in LUAD cells. Our results not only provide a possible mechanism underlying the AIM2‐promoted metastatic progression and immune evasion of LUAD but also offer a new strategy for combating metastatic/immunosuppressive LUAD via targeting AIM2 activity.

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“…For example, it is known that cigarette smoking is one of sources of chronic inflammation [ 4 ], which might in turn lead to chronic obstructive pulmonary disease (COPD) or cancer. Cigarette smoking has been also linked to differences in response to immunotherapy [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. Thus, in order to better understand the process of emergence of lung diseases, it is important to develop computational approaches, which, while leveraging existing data, can help to untangle the impact of various factors on molecular changes in lung tissue.…”

Section: Introductionmentioning

confidence: 99%

Mutational Signatures as Sensors of Environmental Exposures: Analysis of Smoking-Induced Lung Tissue Remodeling

et al. 2022

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Smoking is a widely recognized risk factor in the emergence of cancers and other lung diseases. Studies of non-cancer lung diseases typically investigate the role that smoking has in chronic changes in lungs that might predispose patients to the diseases, whereas most cancer studies focus on the mutagenic properties of smoking. Large-scale cancer analysis efforts have collected expression data from both tumor and control lung tissues, and studies have used control samples to estimate the impact of smoking on gene expression. However, such analyses may be confounded by tumor-related micro-environments as well as patient-specific exposure to smoking. Thus, in this paper, we explore the utilization of mutational signatures to study environment-induced changes of gene expression in control lung tissues from lung adenocarcinoma samples. We show that a joint computational analysis of mutational signatures derived from sequenced tumor samples, and the gene expression obtained from control samples, can shed light on the combined impact that smoking and tumor-related micro-environments have on gene expression and cell-type composition in non-neoplastic (control) lung tissue. The results obtained through such analysis are both supported by experimental studies, including studies utilizing single-cell technology, and also suggest additional novel insights. We argue that the study provides a proof of principle of the utility of mutational signatures to be used as sensors of environmental exposures not only in the context of the mutational landscape of cancer, but also as a reference for changes in non-cancer lung tissues. It also provides an example of how a database collected with the purpose of understanding cancer can provide valuable information for studies not directly related to the disease.

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Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non‐small cell lung cancer

Cited by 11 publications

References 30 publications

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

Smoking Status and Survival in Patients With Early-Stage Primary Cutaneous Melanoma

AIM2 upregulation promotes metastatic progression and PD‐L1 expression in lung adenocarcinoma

Mutational Signatures as Sensors of Environmental Exposures: Analysis of Smoking-Induced Lung Tissue Remodeling

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