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

Laura P. Stabile; Vinod Kumar; Autumn Gaither-Davis; Eric H.B. Huang; Frank P. Vendetti; Princey Devadassan; Sanja Dacic; Riyue Bao; Richard A. Steinman; Timothy F. Burns; Christopher J. Bakkenist

doi:10.1172/jci.insight.145307

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

Laura P. Stabile,¹ Vinod Kumar,² Autumn Gaither-Davis,² Eric H.B. Huang,² Frank P. Vendetti,³ Princey Devadassan,² Sanja Dacic,⁴ Riyue Bao,² Richard A. Steinman,² Timothy F. Burns,¹ and Christopher J. Bakkenist³

Published December 22, 2020 - More info

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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 (NNK) 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 >500. FVBW-17 cells transplanted subcutaneously, via tail vein and orthotopically generated tumors in FVB/N mice that were histologically similar to human LUAD. FVBW-17 tumors expressed PD-L1, were infiltrated with CD8+ T cells, and responsive to anti-PD-L1 therapy. FVBW-17 cells were also engineered to express green fluorescent protein and luciferase to facilitate the detection and quantification of tumor growth. Distant metastases to lung, spleen, liver, and kidney were observed from subcutaneously transplanted tumors. This novel cell line is a robust representation of human smoking-related LUAD biology and provides a much needed pre-clinical model in which to test promising new agents and combinations including immune-based therapies.

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

Laura P. Stabile,¹ Vinod Kumar,² Autumn Gaither-Davis,² Eric H.B. Huang,² Frank P. Vendetti,³ Princey Devadassan,² Sanja Dacic,⁴ Riyue Bao,² Richard A. Steinman,² Timothy F. Burns,¹ and Christopher J. Bakkenist³

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

Laura P. Stabile,1 Vinod Kumar,2 Autumn Gaither-Davis,2 Eric H.B. Huang,2 Frank P. Vendetti,3 Princey Devadassan,2 Sanja Dacic,4 Riyue Bao,2 Richard A. Steinman,2 Timothy F. Burns,1 and Christopher J. Bakkenist3

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Laura P. Stabile,¹ Vinod Kumar,² Autumn Gaither-Davis,² Eric H.B. Huang,² Frank P. Vendetti,³ Princey Devadassan,² Sanja Dacic,⁴ Riyue Bao,² Richard A. Steinman,² Timothy F. Burns,¹ and Christopher J. Bakkenist³