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- Title
Promising immunotherapeutic strategies based on different immune characteristics of tumor-infiltrating lymphocytes according to molecular classification in endometrial cancer.
- Authors
Jung-Yun Lee; Jung Chul Kim; Miran Lee; JooHyang Lee; Yong Jae Lee; Sunghoon Kim; Sang Wun Kim; Junsik Park
- Abstract
Objective: This study aims to identify distinct immune characteristics of tumor-infiltrating lymphocytes (TILs) according to molecular classification for an optimal therapeutic strategy in endometrial cancer. Methods: We isolated peripheral blood mononuclear cells and TILs from 81 patients. The expression of immune checkpoint receptors (ICRs) and T-cell transcription factors of TILs were examined using flowcytometry. Fourteen fresh frozen tumor tissues were processed for bulk RNA sequencing. The formalin-fixed, paraffin-embedded biopsies of patients (n=66) were evaluated according to the ProMisE algorithm based on immunohistochemistry for mismatch repair (MMR) proteins and p53, sequencing for the presence of POLE mutations; POLE-mutated (POLE), MMR deficient (MMRd), p53-abnormal (p53abn), and non-specific molecular profile (NSMP). Results: Immune exhausted genes (PDCD1, CTLA-4, TIGIT, TOX, ENTPD-1) are upregulated in high mutational load group (POLE MMRd). In gene set enrichment analysis, upregulated gene sets in regulatory T (Treg) cells (GSE14415) were enriched in POLE MMRd. Sixty-six tumors were classified to POLE (n=6), MMRd (n=17), NSMP (n=23) and p53abn (n=20). CD8 TILs of POLE MMRd showed higher expression of ICRs (PD-1, TIM-3, CD39, TOX) than those of NSMP and p53abn, also, lower expression of TCF-1. CTLA-4 , TIGIT Treg cells were more infiltrated in MMRd than NSMP. Immune exhausted markers (PD-1, TIGIT, CD39, TOX, CD101) are enriched in CD8 TILs of L1CAM( ) NSMP than those of L1CAM(-) NSMP. Conclusion: CD8 TILs of POLE MMRd highly expressed ICRs and were more exhausted compared to those of others, providing evidence for immunotherapy. TIGIT and PD-1 blockade for L1CAM( ) NSMP were considered promising. there is needed for clinical trials to optimize immunotherapy according to molecular subtypes.
- Subjects
ENDOMETRIAL cancer; TUMOR-infiltrating immune cells; MONONUCLEAR leukocytes; GENETIC load; BIOMARKERS
- Publication
Journal of Gynecologic Oncology, 2024, Vol 35, p27
- ISSN
2005-0380
- Publication type
Academic Journal
- DOI
10.3802/jgo.2024.35.S2.P12