التفاصيل البيبلوغرافية
| العنوان: |
Sepsis-Induced State of Immunoparalysis Is Defined by Diminished CD8 T Cell-Mediated Antitumor Immunity. |
| المؤلفون: |
Danahy, Derek B.1,2, Kurup, Samarchith P.2, Winborn, Christina S.1, Jensen, Isaac J.1,2, Harty, John T.1,2,3, Griffith, Thomas S.4, Badovinac, Vladimir P.1,2,3 vladimir-badovinac@uiowa.edu |
| المصدر: |
Journal of Immunology. 8/1/2019, Vol. 203 Issue 3, p725-735. 11p. |
| مصطلحات موضوعية: |
*CELLULAR immunity, *PROGRAMMED cell death 1 receptors, *EARLY detection of cancer, *T cells, *TUMOR growth, *INDUCED labor (Obstetrics) |
| مستخلص: |
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-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. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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