IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines

Na Young Song, Xin Li, Buyong Ma, Jami Willette-Brown, Feng Zhu, Chengfei Jiang, Ling Su, Jyoti Shetty, Yongmei Zhao, Gongping Shi, Sayantan Banerjee, Xiaolin Wu, Bao Tran, Ruth Nussinov, Michael Karin, Yinling Hu

Research output: Contribution to journalArticlepeer-review

Abstract

The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/cRel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.

Original languageEnglish
Article numbere2120956119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number6
DOIs
StatePublished - 8 Feb 2022
Externally publishedYes

Keywords

  • Immunosuppressive response
  • Inflammation
  • Lung cancer
  • NK-κB signaling
  • Treg cells

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