Abstract 4615: Differential immune characteristics and anti-PD-1-induced reinvigoration capacity of tumor-infiltrating lymphocytes according to ProMisE classifier in endometrial cancer
Authors: Kim Jung Chul , Park Junsik , Lee Yong Jae , Kim Sunghoon , Kim Sang Wun , Lee Jung-Yun 
Published: April 2023

Abstract
Endometrial cancer (EC), one of the most common gynecological malignancies, has been gradually increasing worldwide. The Cancer Genome Atlas endometrial collaborative project discovered 4 distinct prognostic genomic subtypes, and the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) was developed: POLE-mutated, mismatch repair deficiency (MMR-D), non-specific molecular profile (NSMP), and p53-abnormal (p53abn). In the era of immunotherapy, immune checkpoint inhibitors (ICIs) become a definite management of EC, both as single agent or in combination with other targeted agents. However, the characteristics of the tumor immune microenvironment according to molecular classification in EC are not well known. This study was conducted to identify distinct immune properties of tumor infiltrating lymphocytes (TILs) according to molecular classification in EC and find optimal therapeutic targets in each molecular subtypes. We isolated peripheral blood mononuclear cells (PBMCs) and TILs from 81 patients with EC. The expression of immune checkpoint receptors and T-cell transcription factors of TILs were examined using flow cytometry. Sixty-six patients were evaluated according to the ProMisE algorithm based on sequencing for the presence of POLE mutations, immunohistochemistry for MMR proteins and p53 (POLE-mut, n=6; MMR-D, n=17; p53abn, n=20; NSMP, n=23). Tumors were categorized into one of the four molecular subtypes. TILs were ex vivo stimulated with anti-CD3 in the presence of anti-PD-1, and their proliferation was assessed to predict ICI-induced reinvigoration capacity of CD8 TILs. Comparing T-cell transcription factors (TCF-1 and TOX), CD8 TILs showed higher expression of TOX, and lower expression of TCF-1. When comparing the immune characteristics of TILs according to molecular subtypes, Tregs of POLE-mut showed significantly lower expression of CTLA-4 and Ki-67 than that of MMR-D. In addition, CD8 TILs of MMR-D showed higher expression of immune checkpoint receptors, including PD-1, CTLA-4, and TIM-3, and lower expression of TCF-1 than those of p53abn. CD8+TILs of p53abn showed significantly higher expression of CD226 than those of MMR-D. In particular, the frequency of antigen reactive CD39+CD103+CD8 T cells significantly lower in p53abn than in MMR-D. CD8 TILs of NSMP showed higher expression of TOX than those of MMR-D. In ex vivo T cell proliferation assay (n=49), 80.0% POLE-mut (4 of 5), 46.2% MMR-D (6 of 13), 35.7% p53abn (5 of 14) and 35.36% NSMP (6 of 17) showed enhanced proliferation of CD8 TILs upon anti-PD-1 treatment. In endometrial cancer, TILs showed distinct immune properties according to ProMisE classification. Further study is needed to develop optimal treatment targets for the p53abn and NSMP subtype, which is non-immunogenic and hardly reinvigorated by ICIs.
Citation Format: Jung Chul Kim, Junsik Park, Yong Jae Lee, Sunghoon Kim, Sang Wun Kim, Jung-Yun Lee. Differential immune characteristics and anti-PD-1-induced reinvigoration capacity of tumor-infiltrating lymphocytes according to ProMisE classifier in endometrial cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4615.