Carcinogen exposure enhances cancer immunogenicity by blocking the development of an immunosuppressive tumor microenvironment
Mei Huang, … , Marjan Azin, Shadmehr Demehri
Mei Huang, … , Marjan Azin, Shadmehr Demehri
Published October 16, 2023
Citation Information: J Clin Invest. 2023;133(20):e166494. https://doi.org/10.1172/JCI166494.
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Research Article Oncology

Carcinogen exposure enhances cancer immunogenicity by blocking the development of an immunosuppressive tumor microenvironment

Abstract

Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell–mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell–dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.

Authors

Mei Huang, Yun Xia, Kaiwen Li, Feng Shao, Zhaoyi Feng, Tiancheng Li, Marjan Azin, Shadmehr Demehri

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Figure 1

PyMt cells acquire high immunogenicity upon carcinogen exposure.

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PyMt cells acquire high immunogenicity upon carcinogen exposure. (A) Sch...
(A) Schematic diagram of DMBA3-4 and DMSO3-1 cell clones derived from DMBA and DMSO (vehicle control) exposed PyMt cell line, respectively. (B and C) DMBA3-4 and DMSO3-1 tumor kinetics in syngeneic WT C57BL/6 mice shown as (B) tumor growth over time (n = 10 per group) and (C) animal survival rate (n = 6 per group). (D) Representative macroscopic and H&E-stained histological images of DMBA3-4 and DMSO3-1 tumor injection sites in WT mice when DMSO3-1 tumors reach terminal size. Note the absence of any DMBA3-4 tumor in the s.c. fat pad. Scale bars: 1 cm, mouse; 100 μm, histology. (E and F) DMBA3-4 and DMSO3-1 tumor kinetics in syngeneic Rag1KO mice shown as (E) tumor growth over time (n = 12 for DMBA3-4 and n = 10 for DMSO3-1 group) and (F) mouse survival rate (n = 6 for DMBA3-4 and n = 5 for DMSO3-1 group). (G) DMBA3-4 tumor growth in WT mice treated with anti-CD8β, anti-CD4 depleting antibody alone or the combination of anti-CD8β and anti-CD4 antibodies (n = 6 per group). (H and I) Lung metastasis of DMBA3-4 and DMSO3-1 cells shown as (H) representative H&E-stained histological images of the lung (scale bar: 1 mm) and (I) percent lung surface area occupied by tumor foci at day 21 after i.v. injection of 200,000 cells per mouse (n = 5 per group). (J) BaP-4 and DMSO-1 tumor growth in syngeneic WT C57BL/6 mice (n = 6 per group). (K) BaP-4 tumor growth in WT mice treated with anti-CD8β and anti-CD4 combination antibodies versus IgG control antibody (n = 6 per group). Mice received 100,000 cancer cells per orthotopic injection site. 2-way ANOVA (B, E, G, J, and K), unpaired t test (I) and log-rank test (C and F), bar graph shows mean + SD.