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.
Bibliographical noteFunding Information:
This work was supported by National Institutes of Health Grants GM113961 (to V.P.B.), GM115462 (to T.S.G.), T32AI007485 (to D.B.D. and I.J.J.), and T32AI007511 (to I.J.J.), the Holden Comprehensive Cancer Center at the University of Iowa and its National Cancer Institute Award P30CA086862 (to V.P.B.), and a Veterans Administration Merit Review Award I01BX001324 (to T.S.G.).
Copyright Ó 2019 by The American Association of Immunologists, Inc.