PD-1 blunts the function of ovarian tumor-infiltrating dendritic cells by inactivating NF-κB

Lavakumar Karyampudi, Purushottam Lamichhane, James Krempski, Kimberly R. Kalli, Marshall D. Behrens, Doris M. Vargas, Lynn C. Hartmann, Jo Marie T. Janco, Haidong Dong, Karen E. Hedin, Allan B. Dietz, Ellen L. Goode, Keith L. Knutson

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell-dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c+CD11b+CD8-CD209a+) and human (CD1c+CD19-) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB- dependent cytokine release in a SHP-2-dependent manner. Conversely, inhibition of NF-κB-mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer.

Original languageEnglish (US)
Pages (from-to)239-250
Number of pages12
JournalCancer research
Volume76
Issue number2
DOIs
StatePublished - Jan 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Karyampudi, L., Lamichhane, P., Krempski, J., Kalli, K. R., Behrens, M. D., Vargas, D. M., Hartmann, L. C., Janco, J. M. T., Dong, H., Hedin, K. E., Dietz, A. B., Goode, E. L., & Knutson, K. L. (2016). PD-1 blunts the function of ovarian tumor-infiltrating dendritic cells by inactivating NF-κB. Cancer research, 76(2), 239-250. https://doi.org/10.1158/0008-5472.CAN-15-0748