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

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 and Vladimir P Badovinac
The Journal of immunology (1950), Vol.203(3), pp.725-735
08/01/2019
DOI: 10.4049/jimmunol.1900435
PMCID: PMC6650357
PMID: 31189573

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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-1 ) 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-1 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-1 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.
 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 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

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