J Cancer 2022; 13(2):413-425. doi:10.7150/jca.65400 This issue

Research Paper

Impacts of Cigarette Smoking on the Tumor Immune Microenvironment in Esophageal Squamous Cell Carcinoma

Geng Wang2, Chuqing Pan3, Kexin Cao1, Jingbing Zhang1, Hui Geng1, Kusheng Wu1, Jing Wen3,4✉, Caixia Liu1✉

1. Department of Preventive Medicine, Shantou University Medical College, Shantou, Guangdong, China.
2. Department of Thoracic Surgery, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China.
3. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
4. Guangdong Esophageal Cancer Research Institute, Guangzhou, China.
*Wen and Liu have contributed equally to this work.

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Citation:
Wang G, Pan C, Cao K, Zhang J, Geng H, Wu K, Wen J, Liu C. Impacts of Cigarette Smoking on the Tumor Immune Microenvironment in Esophageal Squamous Cell Carcinoma. J Cancer 2022; 13(2):413-425. doi:10.7150/jca.65400. Available from https://www.jcancer.org/v13p0413.htm

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Abstract

Graphic abstract

Objective: Cigarette smoking is a carcinogenic factor for esophageal cancer and evidence also indicates its effects on tumor microenvironment in patients with esophageal squamous cell carcinoma (ESCC).

Materials and Methods: In our study, we demonstrated nine immune infiltrating cells and markers in non-smokers and smokers of 189 non-drinking ESCC patients with multiplex fluorescent immunohistochemistry (mflHC) staining and multispectral imaging. The impacts of cigarette smoking on tumor microenvironment and patient prognosis were also analyzed.

Results: Among 189 ESCC patients of non-drinker, 86 patients was current smokers, while 34 males and 59 females were non-smokers and 10 former-smokers. Among 34 male non-smokers and 83 smokers, distinct immune infiltrating cells, with increased DCs in stromal regions (P=0.033), elevated infiltration of Treg cells in intraepithelial regions (P=0.010) and reduced activate cytotoxic T lymphocytes (aCTLs) in both intraepithelial (P=0.021) and stromal regions (P=0.017), were observed in tumor specimens of smoking males, implying an immune suppressed response during cigarette smoke exposure. For smoking characters, the level of stromal tumor-associated macrophages (TAMs) infiltration was correlated with smoking year after age adjusted (rs=0.352, P=0.002). Though cigarette smoking did not alter the expression of programmed death ligand 1 (PD-L1) in epithelial cells or TAMs in tumor specimens, higher expression of PD-L1 predicted a worse survival in non-smokers but not smokers.

Conclusions: Our findings indicated smoking may impair T cell-mediated immune response and supported the possible impacts of cigarette smoking in PD-L1 related research and therapy of ESCC.

Keywords: Cigarette smoking, Esophageal squamous cell carcinoma, Immune infiltration, PD-L1, Tumor microenvironment