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

Abstract

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.

• Authors: Jacob Curley, Mark R Conaway, Zachary Chinn, Linda Duska, Mark Stoler, Anne M Mills
• Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc (Mod Pathol) Vol. 33 Issue 6 Pg. 1182-1192 (06 2020) ISSN: 1530-0285 [Electronic] United States
• PMID: 32139873 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• Galectins
• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• LGALS9 protein, human

Topics

• Adult
• B7-H1 Antigen (metabolism)
• Biomarkers, Tumor (metabolism)
• Carcinoma, Squamous Cell (metabolism, pathology)
• Female
• Galectins (metabolism)
• Hepatitis A Virus Cellular Receptor 2 (metabolism)
• Humans
• Lymphocytes, Tumor-Infiltrating (metabolism, pathology)
• Uterine Cervical Neoplasms (metabolism, pathology)
• Vulvar Neoplasms (metabolism, pathology)