Immune profiling and identification of prognostic immune-related risk factors in human ovarian cancer

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Tumor-induced immune suppression, driven by co-inhibitory receptors on T-cells, impairs the immune system's ability to control cancer.
• Understanding the expression patterns of these inhibitory markers on tumor-infiltrating lymphocytes is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

• To characterize the expression of co-inhibitory receptors (LAG-3, PD-1, TIM-3) on T-cells within the tumor microenvironment of advanced ovarian cancer patients.
• To investigate the correlation between T-cell co-inhibitory receptor expression and clinical outcome.
• To assess the functional status of tumor-infiltrating T-cells and the potential of PD-1 blockade for immune cell reinvigoration.

Main Methods:

• Flow cytometry was used to analyze T-cell populations (CD4+ and CD8+) isolated from blood, ascites, and tumors of 35 advanced ovarian cancer patients.
• Multiplex analysis was performed to quantify 26 soluble factors in the tumor microenvironment.
• Ex vivo T-cell activation assays and PD-1 receptor blockade experiments were conducted.

Main Results:

• Significantly higher expression of LAG-3, PD-1, and TIM-3 was observed on T-cells in tumor and ascites compared to blood.
• Intratumoral CD8+ T-cells showed predominant co-expression of these receptors, with PD-1 and TIM-3 being the most common combination.
• Higher proportions of CD8+ T-cells lacking these co-inhibitory receptors correlated with improved overall survival, identifying eight immune-related risk factors.
• Ex vivo analysis confirmed T-cell functionality (IFN-γ, IL-2, TNF-α, IL-17 production) and demonstrated increased IFN-γ release upon PD-1 blockade.

Conclusions:

• The ovarian tumor microenvironment is characterized by inflammation and T-cell dysfunction due to high expression of inhibitory checkpoints.
• Subsets of CD8+ T-cells exhibit dual and triple co-inhibitory receptor expression, suggesting the need for combination therapies targeting multiple checkpoints.
• Restoring T-cell function through strategies like PD-1 blockade holds promise for overcoming immune evasion in ovarian cancer.