Abstract 4467: Plasmacytoid dendritic cells, prevalent in the TME of smokers, is associated with a good prognosis and treatment response of LUAD
Authors: Kim Eun Young , Cha Yoon Jin , Choi Yong Jun , Park Min Kyung , Chang Yoon Soo 
Published: April 2023

Background: Attempts to find therapeutic biomarkers through investigation of subgroup showing good responses to certain drugs in cancer often yielded meaningful results. Smoker’s lung adenocarcinoma has consistently shown a favorable response to immune checkpoint inhibitors (ICIs) than non-smoker’s lung adenocarcinoma. Comparing the macrophages (Mϕ) and dendritic cells (DC) constituting the innate immune tumor microenvironment (TME) in lung cancer of smokers and nonsmokers, we tried to figure out the difference in TME and biomarkers that predict the therapeutic response to ICIs.

Methods: The inflammatory TME of current and never smokers’ lung cancer was explored by tumor and adjacent normal appearing lung tissues (Tu and NL hereafter) scRNA sequencing and verified by IF, IHC, and open-source dataset.

Results: Compared to lungs of nonsmokers, smokers’ lung have an increased proportion of cell populations involved in innate immunity, and the increased cell population was mostly Mϕ, which were enriched in NL. When the number of Mϕ present in the NL of the corresponding individual were taken as the denominator, Tu of smokers has a lower proportion of Mϕ than that of non-smokers. Further sub-clustering of Mϕ and DCs showed that FCN1-mono and CD163-LGMN Mϕ, which correspond to the initial differentiation into the resident cell population within the tissue, and mo-DC, cDC2, and pDC were significantly enriched in the Tu. Among them, pDC is a functionally differentiated tissue resident cell that showed a different tissue distribution pattern between smokers and non-smokers, so it was estimated as one of the causes of the different treatment response to ICIs between the two patient groups. The difference of pDC’s distribution was further verified through IHC staining using anti-LILRA4 and anti-TLR9 antibody, showing pDC was significantly enriched in the smokers’ TME. A significant increase in TLR9 expression was observed in or around lung cancer immediately after ionizing radiation or cisplatin treatment in LSL-Kras G12D mouse model. The survival analysis of TCGA-LUAD dataset showed that the patients' overexpressing pDC markers such as IRF4 and TLR9 was superior clinical outcomes to the age, gender and smoking matched control group. Comparing the difference in TMB between the top 25% and bottom 25% groups according to the expression of TLR9, it was 5.81/Mb in the upper group and 4.36/Mb in the subgroup, showing a significant difference.

Conclusions: pDC is an innate immune cell population that showed a prominent increase in smokers’ TME compared to that of non-smokers, suggesting that its increase may be one the factors that smokers’ lung cancer show favorable responses to ICI than that of non-smokers. These findings suggest that the pDC signature can be developed as a biomarker predicting the response to ICIs and increasing the number of pDCs or its activity may improve treatment outcome of ICIs.

Citation Format: Eun Young Kim, Yoon Jin Cha, Yong Jun Choi, Min Kyung Park, Yoon Soo Chang. Plasmacytoid dendritic cells, prevalent in the TME of smokers, is associated with a good prognosis and treatment response of LUAD. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4467.