Syngeneic tobacco carcinogen–induced mouse lung adenocarcinoma model exhibits PD-L1 expression and high tumor mutational burden

Abstract

Human lung adenocarcinoma (LUAD) in current or former smokers exhibits a high tumor mutational burden (TMB) and distinct mutational signatures. Syngeneic mouse models of clinically relevant smoking-related LUAD are lacking. We established and characterized a tobacco-associated, transplantable murine LUAD cell line, designated FVBW-17, from a LUAD induced by the tobacco carcinogen 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in the FVB/N mouse strain. Whole-exome sequencing of FVBW-17 cells identified tobacco-associated Kras G12D and Trp53 mutations and a similar mutation profile to that of classic alkylating agents with a TMB greater than 500. FVBW-17 cells transplanted subcutaneously, via tail vein, and orthotopically generated tumors that were histologically similar to human LUAD in FVB/N mice. FVBW-17 tumors expressed programmed death ligand 1 (PD-L1), were infiltrated with CD8 + T cells, and were responsive to anti–PD-L1 therapy. FVBW-17 cells were also engineered to express green fluorescent protein and luciferase to facilitate detection and quantification of tumor growth. Distant metastases to lung, spleen, liver, and kidney were observed from subcutaneously transplanted tumors. This potentially novel cell line is a robust representation of human smoking-related LUAD biology and provides a much needed preclinical model in which to test promising new agents and combinations, including immune-based therapies.

Smoking signature is superior to programmed death-ligand 1 expression in predicting pathological response to neoadjuvant immunotherapy in lung cancer patients

“…Currently, PD-L1, TMB (24), and MSI (25) represent the only clinically approved biomarkers predicting the therapeutic benefits of ICIs. Smoking could induce an increased rate of mutated proteins or neoantigens in lung cancer (26)(27)(28). In support of this, mining of TCGA lung cancer cohort showed that heavy smoking is associated with high TMB (26)(27)(28) and MSI (29,30) (Figure 1F), which could partially explain the high degree of response in the heavy smokers.…”

“…Smoking could induce an increased rate of mutated proteins or neoantigens in lung cancer (26)(27)(28). In support of this, mining of TCGA lung cancer cohort showed that heavy smoking is associated with high TMB (26)(27)(28) and MSI (29,30) (Figure 1F), which could partially explain the high degree of response in the heavy smokers. Along the same lines, univariate and multivariate analyses showed that high TMB was significantly associated with immunotherapy in NSCLC patients (Figure 1G).…”

“…Instead, we found out that the smoking was likely to increase TMB/MSI, another two approved biomarkers for immunotherapy response, consequently increasing the response to immunotherapy (Figure 1F,1G). Supporting this notion, recent evidence also revealed the association between heavy smoking and TMB (26)(27)(28) and MSI (29,30) in the corresponding tumors (Figure 1), since clinical trialbased evidence has demonstrated that TMB is linked to the pathological response to ICIs (18). Despite this, TMB is complex, and its related data are not available in real-time for decision-making in the first-line setting.…”

Neoadjuvant immunotherapy facilitates resection of surgically-challenging lung squamous cell cancer

“…Gainor et al retrospectively analyzed a cohort of NSCLC patients treated with ICIs, there is a dramatic difference in the overall response rate in heavy smokers, compared with that in light or never smokers (20.6% vs. 4.2%) (33). Mechanistically, smoking could lead to high TMB and/or PD-L1 (34)(35)(36), which, at least partially, explains the association between heavy smoking history and high response rate to ICIs treatment. Further studies are warranted to investigate the mechanistic links of heavy smoking history with the response to ICIs treatment.…”

Targeting the ERβ/HER Oncogenic Network in KRAS Mutant Lung Cancer Modulates the Tumor Microenvironment and Is Synergistic with Sequential Immunotherapy

“…Here, we evaluated the immunomodulatory effects of F+D in vitro and in vivo using the novel syngeneic KRAS+ murine lung cancer model, FVBW-17, derived from a lung adenocarcinoma induced by exposure of an FVB/N mouse to the tobacco carcinogen NNK [ 11 ]. KRAS + lung cancer is known to be dependent on HER2/HER3 signaling [ 12 , 13 ] and often express ERβ [ 7 , 14 ], making it potentially responsive to a pan-HER inhibitor in combination with an ER blocker.…”