Sepsis-Induced State of Immunoparalysis Is Defined by Diminished CD8 T Cell-Mediated Antitumor Immunity

J Immunol. 2019 Aug 1;203(3):725-735. doi: 10.4049/jimmunol.1900435. Epub 2019 Jun 12.

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-γ production, and survival compared with sham counterparts. To increase the frequency and/or functional capacity of PD-1hi CD8 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-1hi CD8 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.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antigens, CD / immunology
  • Antigens, CD / metabolism*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cecum / surgery
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Female
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocyte Count
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Male
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism*
  • Sepsis / immunology*

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, mouse