Nrf2-Deficient Mice show Unfavorable Immune Signature in Advanced Lung Tumors
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 consequences of Nrf2 activation in cells during lung carcinogenesis are poorly characterized and may 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 by vinyl carbamate.
Outcomes: Nrf2 KO mice developed lung tumors earlier than the WT mice also exhibited larger and more tumors with 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. Additionally, 34 immune response genes were significantly upregulated in tumors in Nrf2 KO mice, particularly a collection of cytokines (Cxcl1, Csf1, Ccl9, Cxcl12, etc.) and major histocompatibility complex antigens that promote tumor growth.
Innovation: Our research found a novel immune signature, characterized by the infiltration of both tumor-promoting resistant cells, raised cytokines, and increased expression of immune response genes in the tumors and lungs of Nrf2 KO mice. A complementary profile was also found in lung cancer patients, encouraging the clinical significance of our findings.
Conclusion: Overallour results confirmed a protective role for Nrf2 at late-stage carcinogenesis and, abruptly, imply that activation of Nrf2 in immune cells might be advantageous for treating or preventing lung cancer. Antioxid. Redox Signal.Details: Nrf2; resistant signature; inflammatory cytokines; lung carcinogenesis; vinyl carbamate.