Abstract
TIGIT is a recently identified coinhibitory receptor that is upregulated in the setting of cancer and functionally contributes to the impairment of antitumor immunity. However, its role during sepsis is unknown. Because patients with cancer are 10 times more likely to die of sepsis than previously healthy (PH) patients with sepsis, we interrogated the role of TIGIT during sepsis in the context of preexistent malignancy. PH mice or cancer (CA) mice inoculated with lung carcinoma cells were made septic by cecal ligation and puncture (CLP). We found that sepsis induced TIGIT upregulation predominantly on Tregs and NK cells in both PH and CA mice. Anti-TIGIT Ab improved the 7-d survival of CA septic mice but not PH mice after CLP. Treatment of CA septic animals but not PH septic animals with anti-TIGIT mAb significantly reversed sepsis-induced loss of CD4+ T cells, CD8+ T cells, Foxp3+ Treg, and CD19+ B cells in the spleen, which was the result of decreased caspase-3+ apoptotic cells. In sum, we found that anti-TIGIT Ab reversed sepsis-induced T cell apoptosis in CA septic mice and led to a significant survival benefit, suggesting its use as a potential immunotherapy to improve outcomes in septic patients with cancer.
Highlights
Sepsis is a life-threatening condition of multiorgan dysfunction resulting from a dysregulated host response to infection [1]
In previously healthy (PH) mice, TIGIT was upregulated on total CD4+ T cells, Foxp3+ Treg, CD4+ Foxp3– T conventional cells (Tconvs), and NK cells on days 2 and 3 after sepsis compared with sham controls (Figure 1, A and B)
TIGIT was upregulated on B cells by day 3 after cecal ligation and puncture (CLP), overall expression was negligible compared with other cell populations
Summary
Sepsis is a life-threatening condition of multiorgan dysfunction resulting from a dysregulated host response to infection [1]. Sepsis remains a critical problem with substantial morbidity and mortality. This is evidenced by results from a 2020 Lancet study demonstrating that approximately 20% of the world’s population dies from complications of sepsis [2], and that sepsis-related healthcare costs amount to approximately $60 billion per year in the United States alone [3]. Accumulating evidence has revealed that immunosuppression plays a pivotal role in the progress and prognosis of sepsis [5] This immunosuppressive state manifests as a decrease in both the number and functionality of immune cells and the upregulation of T cell coinhibitory receptors [6]. Immunotherapies directed against these coinhibitory receptors have exhibited unprecedented benefit in clinical trials for multiple types of cancer [11]
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