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Published on: February 9, 2014
TIGIT modulates sepsis-induced immune dysregulation in mice with preexisting malignancy
Wenxiao Zhang1,2, Jerome C Anyalebechi1, Kimberly M Ramonell1
1Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.
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.
Insights
Blocking TIGIT (T cell immunoglobulin and ITIM domain) immunotherapy improved survival in septic mice with cancer. This treatment reduced T cell death, offering a potential strategy for cancer patients experiencing sepsis.
Area of Science:
- Immunology
- Oncology
- Critical Care Medicine
Background:
- TIGIT (T cell immunoglobulin and ITIM domain) is a coinhibitory receptor implicated in impaired antitumor immunity.
- The role of TIGIT in sepsis, particularly in cancer patients who have a higher mortality risk, remains unexplored.
Purpose of the Study:
- To investigate the role of TIGIT in sepsis among mice with pre-existing cancer.
- To evaluate the therapeutic potential of anti-TIGIT antibody treatment in this context.
Main Methods:
- Cancer (CA) and previously healthy (PH) mice underwent cecal ligation and puncture (CLP) to induce sepsis.
- TIGIT expression on immune cells was analyzed.
- Survival rates and immune cell populations (T cells, Tregs, B cells) in the spleen were assessed after anti-TIGIT antibody treatment.
Main Results:
- Sepsis upregulated TIGIT on Tregs and NK cells in both PH and CA mice.
- Anti-TIGIT antibody improved 7-day survival specifically in septic CA mice, not PH mice.
- Treatment reversed sepsis-induced loss of CD4+ T cells, CD8+ T cells, Tregs, and B cells in CA mice by decreasing apoptosis.
Conclusions:
- TIGIT plays a critical role in sepsis-associated immune dysfunction in the context of cancer.
- Anti-TIGIT antibody therapy demonstrates significant survival benefits in septic cancer mice by preserving T cell populations.
- Targeting TIGIT represents a promising immunotherapy for improving outcomes in cancer patients with sepsis.
