Abstract
Ovarian cancer (OC) is the fifth‐leading cause of cancer‐related death in women with a pathogenesis involving activation of regulatory T cells (Tregs). The T‐cell immunoglobulin and ITIM domain (TIGIT) is a well‐known immune checkpoint molecule that inhibits T‐cell responses. However, the role of TIGIT in OC is not comprehensively understood. In this study, we revealed crucial functions of TIGIT in the development and progression of OC. ID8 cells were used to establish a murine OC model. TIGIT expression was increased in immune cells of OC mice, particularly in CD4+ Tregs. Anti‐TIGIT monoclonal antibodies (mAb) were used to block the function of TIGIT in OC mice, and we found that the anti‐TIGIT treatment reduced the proportion of CD4+ Tregs, but did not affect CD4+ and CD8+ T cells or natural killer cells. Splenic CD4+ Tregs from OC mice were isolated after the anti‐TIGIT treatment, and their functioning was examined. Inhibition of TIGIT lowered the degree of immunosuppression induced by CD4+ Tregs. A survival curve suggested that anti‐TIGIT treatment can improve the survival rate of OC in mice. We conclude that TIGIT enhanced CD4+ Tregs response and mediated immunosuppression in the OC model. Our data suggest that inhibition of TIGIT is a potential therapeutic target in OC patients.
Highlights
Ovarian cancer (OC), the fifth-leading cause of cancer-related death in women, was diagnosed in 22 240 patients and led to an estimated 14 070 deaths in the United States in 2018.1 This high lethality of OC is primarily due to limited infrequency of screening and unspecific symptoms, resulting in diagnosis only at an advanced stage (International Federation of Gynecology and Obstetrics stage III and IV)
Approximately 80% of OC patients initially respond to chemotherapy, more than 60% suffer a relapse with fatal outcome.[4]
Our results showed that anti-T-cell immunoglobulin and ITIM domain (TIGIT) treatment reduced the proportions of CD4+CD25+Foxp3+ Tregs, compared to the control, whereas not effect on CD4+, CD8+ T cells, and NK1.1+ natural killer (NK) cells was observed
Summary
Ovarian cancer (OC), the fifth-leading cause of cancer-related death in women, was diagnosed in 22 240 patients and led to an estimated 14 070 deaths in the United States in 2018.1 This high lethality of OC is primarily due to limited infrequency of screening and unspecific symptoms, resulting in diagnosis only at an advanced stage (International Federation of Gynecology and Obstetrics stage III and IV). Some tumors primarily arise from tissues which are not present in the ovary under normal conditions.[5] Infiltration of more effector T cells and fewer regulatory T cells (Tregs) into OCs was shown to be strongly associated with better chances of survival.[6] T cells are activated by co-regulatory signals to enhance antitumor immune responses when tumor antigens occur. Negative checkpoints such as PD-1/PD-L1 and CTLA-4 can be activated during OC and subsequently suppress antitumor immune responses. We found evidence of TIGIT to increase CD4+ Tregs responses, and blocking of TIGIT exerted therapeutic effects in an OC model
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