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Identification of an Unfavorable Immune Signature in Advanced Lung Tumors from Nrf2-Deficient Mice
Di Zhang1, Jonathan Rennhack2, Eran R Andrechek2
11 Department of Pharmacology and Toxicology, Michigan State University , East Lansing, Michigan.
Aims:
Activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in normal cells inhibits carcinogenesis, whereas constitutive activation of Nrf2 in cancer cells promotes tumor growth and chemoresistance. However, the effects of Nrf2 activation in immune cells during lung carcinogenesis are poorly defined and could either promote or inhibit cancer growth. Our studies were designed to evaluate tumor burden and identify immune cell populations in the lungs of Nrf2 knockout (KO) versus wild-type (WT) mice challenged with vinyl carbamate.
Results:
Nrf2 KO mice developed lung tumors earlier than the WT mice and exhibited more and larger tumors over time, even at late stages. T cell populations were lower in the lungs of Nrf2 KO mice, whereas tumor-promoting macrophages and myeloid-derived suppressor cells were elevated in the lungs and spleen, respectively, of Nrf2 KO mice relative to WT mice. Moreover, 34 immune response genes were significantly upregulated in tumors from Nrf2 KO mice, especially a series of cytokines (Cxcl1, Csf1, Ccl9, Cxcl12, etc.) and major histocompatibility complex antigens that promote tumor growth.
Innovation:
Our studies discovered a novel immune signature, characterized by the infiltration of tumor-promoting immune cells, elevated cytokines, and increased expression of immune response genes in the lungs and tumors of Nrf2 KO mice. A complementary profile was also found in lung cancer patients, supporting the clinical significance of our findings.
Conclusion:
Overall, our results confirmed a protective role for Nrf2 in late-stage carcinogenesis and, unexpectedly, suggest that activation of Nrf2 in immune cells may be advantageous for preventing or treating lung cancer. Antioxid. Redox Signal.
Insights
The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway plays a protective role in lung carcinogenesis. Loss of Nrf2 in immune cells promotes tumor growth and alters the immune microenvironment, suggesting Nrf2 activation may be beneficial for cancer prevention and treatment.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- The role of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in lung carcinogenesis is complex, with inhibitory effects in normal cells but promoting effects in established cancers.
- The specific impact of Nrf2 activation within immune cells during lung cancer development remains poorly understood, presenting a critical knowledge gap.
Purpose of the Study:
- To investigate the role of Nrf2 in immune cells during lung carcinogenesis.
- To evaluate tumor burden and characterize immune cell populations in Nrf2 knockout (KO) versus wild-type (WT) mice exposed to a lung carcinogen.
Main Methods:
- Mice lacking Nrf2 (Nrf2 KO) and WT mice were challenged with vinyl carbamate to induce lung tumors.
- Tumor burden, immune cell populations (T cells, macrophages, myeloid-derived suppressor cells), and immune gene expression in lung tissue and tumors were analyzed.
Main Results:
- Nrf2 KO mice exhibited accelerated tumor development with increased tumor number and size compared to WT mice.
- Nrf2 deficiency was associated with reduced T cell populations and elevated levels of tumor-promoting macrophages and myeloid-derived suppressor cells.
- A distinct immune signature was observed in Nrf2 KO mice, including upregulated expression of pro-tumorigenic cytokines and major histocompatibility complex antigens.
Conclusions:
- Nrf2 plays a protective role in late-stage lung carcinogenesis, particularly within the immune system.
- Activation of Nrf2 in immune cells may represent a promising strategy for lung cancer prevention and treatment.
- Findings in mice show a complementary immune profile to that observed in human lung cancer patients, highlighting clinical relevance.
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