Tumor-TME Bipartite Landscape of PD-1/PD-L1 in Endometrial Cancers

• Published in: International journal of molecular sciences 2023-07, Vol.24 (13), p.11079
• Main Authors: Sulaiman, Raed, De, Pradip, Aske, Jennifer C, Lin, Xiaoqian, Dale, Adam, Koirala, Nischal, Gaster, Kris, Espaillat, Luis Rojas, Starks, David, Dey, Nandini
• Format: Article
• Language: English
• Subjects: B7-H1 Antigen - metabolism; Blood vessels; Cancer; cancer-associated fibroblasts; CD8 antigen; Cytotoxicity; Endometrial cancer; Endometrial Neoplasms - genetics; Endometrium; Female; Fibroblasts; Flow cytometry; Gene expression; Humans; Hypotheses; Immune system; Ligands; Lymphocytes; Lymphocytes T; Mesenchyme; mRNA; Myometrium; PD-1 protein; PD-1-PD-L1/L2 landscape in tumor and TME; PD-L1 protein; plasma PD-1; plasma PD-L1/L2; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Protein expression; Proteins; Stromal cells; T cells; tripartite dialogue between tumor-TME-blood; Tumor cells; Tumor microenvironment; Tumor Microenvironment - genetics; tumor-adjacent normal tissue; Tumors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241311079

The bipartite landscape of tumor cells and stromal cells determines a tumor's response to treatment during disease management. In endometrial cancers (ECs), the mechanistic contribution of PD-L1/L2 and PD-1 signaling of the host's tumor microenvironment (TME) (CAF and immune cells) in the context of the tumor cells is elusive. To understand the tumor-stroma-immune crosstalk, we studied the compartmental pattern of PD-L1/L2 and PD-1 expression in EC tissues and their matched CAFs. Over 116 surgically resected tumors (T) and the tumor-adjacent normal tissues (N) were obtained from consented unselected consecutive patients. IHC was performed in T, N-epi-thelium, and the stromal mesenchymal environment (SME; mesenchyme) in the T and N tissues. The staining intensity and distribution patterns of PD-L1/L2 and PD-1 in the FFPE sections of T and N were evaluated by a pathologist using a standard scoring system of TPS and CPS. We tested the PD-L1/L2 and PD-1 immune landscape of tumor-TME pair and normal epithelial-stromal mesenchyme pairs from patients with different grades of disease vis-à-vis their CAF PD-L1 levels. We used qRT-PCR to determine the expressions of mRNAs, while the flow cytometry and ICC determined the level of expression of proteins. We observed higher levels of PD-L1 mRNA and protein expression in primary CAFs from the resected tumor tissue compared to the tumor-adjacent normal tissues. We also determined the expression of patients' soluble PD-L1/L2 as peripheral readouts of PD-L1/L2 and PD-1. As we evaluated the results in the context of their pathological parameters, such as grades, stages, lymphovascular invasion, percentage of myometrial invasion, and dMMR in patients, the dominance of PD-L1 expression in TME was positively correlated to the higher pathological grades of tumors, and its relationship with the dMMR. Since the neutralization of CD8-positive cytotoxic T-cells is PD-L1-dependent, our data indicate that irrespective of the PD-L1 positivity of tumor cells, the PD-L1-positive CAFs can play a critical role in bringing out an additional load of PD-L1 for an effective engagement of PD-1 within a tumor mass.