Looking past PD-L1: expression of immune checkpoint TIM-3 and its ligand galectin-9 in cervical and vulvar squamous neoplasia

• Published in: Modern pathology Vol. 33; no. 6; pp. 1182 - 1192
• Main Authors: Curley, Jacob, Conaway, Mark R., Chinn, Zachary, Duska, Linda, Stoler, Mark, Mills, Anne M.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2020; Elsevier Limited
• Subjects: 13/51; 692/699/67/1517/1371; 692/699/67/1857; Adult; B7-H1 Antigen - metabolism; Biomarkers, Tumor - metabolism; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cervical cancer; Cervix; Female; Galectin-9; Galectins - metabolism; Genital cancers; Hepatitis A Virus Cellular Receptor 2 - metabolism; Human papillomavirus; Humans; Immune checkpoint; Immunotherapy; Laboratory Medicine; Lesions; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Medicine; Medicine & Public Health; Pathology; PD-1 protein; PD-L1 protein; Squamous cell carcinoma; Tumors; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology; Vulvar Neoplasms - metabolism; Vulvar Neoplasms - pathology
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-019-0433-3

Immunotherapies targeting the PD-1/PD-L1 pathway have shown some success in cervical and vulvar squamous cell carcinomas, but little is known about the potential vulnerability of these tumors to other checkpoint inhibitors. TIM-3 is a checkpoint molecule that exerts immunosuppressive function via its interaction with Gal-9. TIM-3 and Gal-9 have been identified on a variety of malignancies but have not been studied in cervical and vulvar cancers, nor has their relationship to PD-L1 been established. Sixty-three cervical and vulvar invasive ( n  = 34) and intraepithelial lesions ( n  = 29) were assessed for TIM-3, Gal-9, and PD-L1 in tumor/lesional cells and associated immune cells. Tumoral TIM-3 expression was identified in 85% of squamous cell carcinomas but only 21% of intraepithelial lesions ( p  < 0.0001). When immune cells were also accounted for, 97% of invasive and 41% of intraepithelial lesions had a TIM-3 combined positive score (CPS) ≥ 1 ( p  < 0.0001). Tumoral membranous expression of Gal-9 was seen in 82% of squamous cell carcinomas and 31% of intraepithelial lesions ( p  = 0.0001); nearly all cases had Gal-9-positive immune cells. Tumoral PD-L1 was seen in 71% of squamous cell carcinomas and 10% of intraepithelial lesions ( p  < 0.0001), while the PD-L1 CPS was ≥1 in 82 and 21%, respectively ( p  < 0.0001). There were no significant differences in TIM-3, GAL-9, or PD-L1 expression in cervical vs. vulvar neoplasms, nor was HPV status significantly associated with any of the three markers. Dual TIM-3/Gal-9 expression was present in the majority (86%) of PD-L1-positive cases including 100% of PD-L1-positive squamous cell carcinomas, suggesting a possible role for TIM-3 checkpoint inhibition in concert with anti-PD-1/PD-L1.