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Sulfisoxazole Elicits Robust Antitumour Immune Response Along with Immune Checkpoint Therapy by Inhibiting Exosomal
Jung Min Shin1,2, Chan-Hyeong Lee3, Soyoung Son1,4
1School of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea.
Abstract:
Despite their potent antitumor activity, clinical application of immune checkpoint inhibitors has been significantly limited by their poor response rates (<30%) in cancer patients, primarily due to immunosuppressive tumor microenvironments. As a representative immune escape mechanism, cancer-derived exosomes have recently been demonstrated to exhaust CD8+ cytotoxic T cells. Here, it is reported that sulfisoxazole, a sulfonamide antibacterial, significantly decreases the exosomal PD-L1 level in blood when orally administered to the tumor-bearing mice. Consequently, sulfisoxazole effectively reinvigorates exhausted T cells, thereby eliciting robust antitumor effects in combination with anti-PD-1 antibody. Overall, sulfisoxazole regulates immunosuppression through the inhibition of exosomal PD-L1, implying its potential to improve the response rate of anti-PD-1 antibodies.
Insights
Sulfisoxazole, an antibacterial drug, reduces immunosuppressive exosomal PD-L1 in mice, reinvigorating T cells. This approach enhances antitumor effects when combined with PD-1 inhibitors, potentially improving cancer treatment response rates.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy (<30%) in cancer patients due to immunosuppressive tumor microenvironments.
- Cancer-derived exosomes, expressing PD-L1, are a key mechanism for immune escape by exhausting CD8+ cytotoxic T cells.
Purpose of the Study:
- To investigate the potential of sulfisoxazole in modulating the immunosuppressive tumor microenvironment.
- To evaluate sulfisoxazole's effect on exosomal PD-L1 levels and its synergistic effect with anti-PD-1 therapy.
Main Methods:
- Oral administration of sulfisoxazole to tumor-bearing mice.
- Measurement of exosomal PD-L1 levels in blood.
- Assessment of T cell exhaustion and reinvigorating effects.
- Evaluation of antitumor efficacy in combination with anti-PD-1 antibody.
Main Results:
- Sulfisoxazole significantly decreased exosomal PD-L1 levels in tumor-bearing mice.
- The drug effectively reinvigorated exhausted CD8+ T cells.
- Combination therapy with sulfisoxazole and anti-PD-1 antibody demonstrated robust antitumor effects.
Conclusions:
- Sulfisoxazole inhibits immunosuppression by reducing exosomal PD-L1.
- This mechanism suggests sulfisoxazole's potential to enhance the clinical response rates of anti-PD-1 antibodies in cancer therapy.
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