Abstract 1347: Novel lung cancer mouse model to study the effects of cigarette smoke on immune therapy

Abstract

Abstract Background: In 2021, 235,760 new cases of lung cancer will be diagnosed in the United States. The treatment regimen of non-small cell lung cancer (NSCLC) has drastically changed owing to the superior anti-cancer effects generated by the immune-checkpoint inhibitor (ICI). However, only a subset of patients experience benefit after receiving ICI. Tumor Mutation Burden (TMB) and PD-L1 expression in tumor cells are known to be potential biomarkers in predicting a patient’s survival and response to ICI. Several studies showed that NSCLC patients with smoking history had a better response than never smokers due to increased TMB caused by carcinogens in cigarette smoke. However, the roles of tumor microenvironment especially immune microenvironment between smokers and never smokers in response to ICI are poorly understood. We hypothesize that the functions of T cells are influenced by the exposure of cigarette smoke prior to the ICI treatment which affect patients’ response to ICI. Method: A cohort of 216 patients diagnosed with NSCLC who had received at least one dosage of Immune Checkpoint Inhibitor (ICI) at Atrium Wake Forest Baptist Hospital were split into three groups: current smokers, former smokers, and never-smokers. Both PFS and OS analyses were performed to examine whether smoking history is correlated with the ICI response. To establish an in vivo model that recapitulates the patients with different smoking history, we treated mice with cigarette extract (CSE) followed by accessing the peripheral T cell functions by FACS analyses using antibodies targeting GZMB, TNF and IFNG. LL/2 and CMT167 cells will be inoculated to those CSE treated mice by flank injection once we observe a stable activation of T cells compared to control group. Tumor growth will be measured and the amount of tumor infiltrated CD4 and CD8 T cells will be examined by immunocytochemistry at the end point. Results: We found it took around 9 weeks of CSE treatment to observe a significant increase of CD8 and CD4 populations in CSE treated mice. We also treated mouse CD8 T cells isolated from the spleen with CSE and observed a strong activation of GZMB, TNF and IFNG by FACS analyses. Future directions: We will test the efficacy of anti-tumor effect of anti-PD-1 ab in tumor bearing mice exposed with or without CSE prior to the immune therapy. We will also establish a mice model that mimics the former smokers by halting the CSE treatment after 9 weeks of CSE exposure followed by examine the amount of memory T cells. We believe our study will provide additional mechanisms of how cigarette smoke affects the response of ICI by affecting the properties of immune cells. Citation Format: Margaret Rose Smith, Yuezhu Wang, Jimmy Ruiz, Jason Grayson, Yin Liu, Fei Xing. Novel lung cancer mouse model to study the effects of cigarette smoke on immune therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1347.