Sepsis-induced state of immunoparalysis is defined by diminished CD8 T cell–mediated antitumor immunity

Derek B. Danahy, Samarchith P. Kurup, Christina S. Winborn, Isaac J. Jensen, John T. Harty, Thomas S. Griffith, Vladimir P. Badovinac

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Patients who survive sepsis experience long-term immunoparalysis characterized by numerical and/or functional lesions in innate and adaptive immunity that increase the host’s susceptibility to secondary complications. The extent to which tumor development/ growth is affected in sepsis survivors remains unknown. In this study, we show cecal ligation and puncture (CLP) surgery renders mice permissive to increased B16 melanoma growth weeks/months after sepsis induction. CD8 T cells provide partial protection in this model, and tumors from sepsis survivors had a reduced frequency of CD8 tumor-infiltrating lymphocytes (TILs) concomitant with an increased tumor burden. Interestingly, the postseptic environment reduced the number of CD8 TILs with high expression of activating/inhibitory receptors PD-1 and LAG-3 (denoted PD-1hi) that define a tumor-specific CD8 T cell subset that retain some functional capacity. Direct ex vivo analysis of CD8 TILs from CLP hosts showed decreased proliferation, IFN-g production, and survival compared with sham counterparts. To increase the frequency and/or functional capacity of PD-1hiCD8 TILs in tumor-bearing sepsis survivors, checkpoint blockade therapy using anti–PD-L1/anti–LAG-3 mAb was administered before or after the development of sepsis-induced lesions in CD8 TILs. Checkpoint blockade did not reduce tumor growth in CLP hosts when therapy was administered after PD-1hiCD8 TILs had become reduced in frequency and/or function. However, early therapeutic intervention before lesions were observed significantly reduced tumor growth to levels seen in nonseptic hosts receiving therapy. Thus, sepsis-induced immunoparalysis is defined by diminished CD8 T cell–mediated antitumor immunity that can respond to timely checkpoint blockade, further emphasizing the importance of early cancer detection in hosts that survive sepsis. The Journal of Immunology, 2019, 203: 725–735.

Original languageEnglish (US)
Pages (from-to)725-735
Number of pages11
JournalJournal of Immunology
Volume203
Issue number3
DOIs
StatePublished - Aug 1 2019

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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