Chemical carcinogens: implications for cancer treatment
Shaofeng Liu, … , Mary Saunders, Tak W. Mak
Shaofeng Liu, … , Mary Saunders, Tak W. Mak
Published October 16, 2023
Citation Information: J Clin Invest. 2023;133(20):e174319. https://doi.org/10.1172/JCI174319.
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Commentary

Chemical carcinogens: implications for cancer treatment

Abstract

Carcinogen exposure has been associated with enhanced cancer immunogenicity that is often attributed to neoantigen generation. However, the broader, neoantigen-independent impact of carcinogens on immune responses to cancer cells remains underexplored. In this issue of the JCI, Huang et al. uncover a mechanism wherein carcinogen-treated cancer cells exhibit an inability to establish an immunosuppressive tumor microenvironment (TME) due to reduced M-CSF expression. Intriguingly, the so-called carcinogen-induced tumor-associated macrophages (TAMs) within this TME exhibited anti-tumor properties instead of the conventional immunosuppressive phenotype. This phenomenon extended to human lung cancers, as evidenced by TAM reprogramming in smokers versus nonsmokers. This study substantially advances our understanding of carcinogen-mediated effects on cancer immunogenicity, potentially redirecting approaches to cancer immunotherapy.

Authors

Shaofeng Liu, Mary Saunders, Tak W. Mak

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Figure 1

Carcinogens reprogram the TME by downregulating cancer cell expression of M-CSF and CD155.

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Carcinogens reprogram the TME by downregulating cancer cell expression o...
Carcinogen exposure was thought to enhance cancer cell immunogenicity mainly by generating a high mutation burden and promoting neoantigen expression. Huang and colleagues found a mechanism separate from neoantigen production. Carcinogen-treated cancer cells reduced their expression of M-CSF and CD155 and increased immunogenicity by reprogramming TAMs within the TME. Carcinogen exposure resulted in the reduced recruitment of TAMs. In addition, TAMs were reprogrammed to express the M1 markers MHC-II, TLRs, and CD86, and proinflammatory mediators including PRF1, GZMB, CXCL9, CXCL10, and CXCL11. These proinflammatory TAMs increased tumor immunogenicity via T cell–mediated cytotoxicity, resulting in cancer cell killing (8).