β-catenin and PD-L1 expression in mismatch repair deficient endometrial carcinomas

Abstract

<jats:sec><jats:title>Introduction</jats:title><jats:p>Predictors of non-response in mismatch repair deficiency cancers are poorly understood. Upregulation of the canonical Wnt pathway has been associated with decreased immune cell infiltration in many cancer types. The relationship between Wnt/β-catenin pathway activation and the programmed death-ligand 1 axis in endometrial cancer remains poorly characterized. This study evaluates β-catenin expression in a well characterized cohort of endometrial cancers by mismatch repair status and programmed death-ligand 1 expression.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Whole sections of formalin-fixed, paraffin embedded tissue from 23 Lynch syndrome-associated carcinomas, 20 mutL homolog-1 (MLH1) promoter hypermethylated carcinomas, and 19 mismatch repair intact carcinomas were evaluated. Immunohistochemistry staining for β-catenin and programmed death-ligand 1 was performed on all cases. Programmed death-ligand 1 expression was scored in both the tumor and the peri-tumoral immune compartment. Tumor staining was classified as positive when membranous (programmed death-ligand 1) staining was present in ≥1% of tumor cells. Immune stromal staining was scored as positive when ≥5% of peritumoral and intratumoral immune cells (including lymphocytes and macrophages) showed reactivity.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Six tumors (6/62, 9.7%) demonstrated nuclear expression of β-catenin (4 were Lynch syndrome-associated, 1 was MLH1 methylated, 1 was mismatch repair intact). The majority of tumors with nuclear β-catenin expression demonstrated concomitant tumoral programmed death-ligand 1 expression (5/6, 83.3%) and were more likely to demonstrate tumoral programmed death-ligand 1 expression compared to tumors without nuclear β-catenin expression (83.3% vs 39.3%, p=0.04). Both tumoral and immune cell expression of programmed death-ligand 1 was statistically significantly associated with mismatch repair deficient tumors.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>Tumors demonstrating nuclear β-catenin expression were more likely to express tumoral programmed death-ligand 1 staining than tumors without nuclear β-catenin expression. Nuclear β-catenin expression could be a potential predictive biomarker for non-response to immune checkpoint inhibition in mismatch repair deficient tumors. Nuclear β-catenin expression status should be considered as a translational endpoint in future clinical trials of immune checkpoint inhibition in endometrial cancer.</jats:p></jats:sec>

The Role of Immunohistochemistry Markers in Endometrial Cancer with Mismatch Repair Deficiency: A Systematic Review

“…A germline mutation was screened in 53 of the articles [ 49 , 50 , 51 , 53 , 54 , 56 , 57 , 61 , 62 , 63 , 64 , 68 , 69 , 70 , 71 , 72 , 74 , 75 , 79 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 92 , 93 , 94 , 96 , 97 , 104 , 106 , 110 , 112 , 113 , 114 , 116 , 119 , 121 , 122 , 123 , 124 , 127 , 128 , 129 , 133 , 136 , 140 ]. The average number of MMRd tumors included was 98.5 (minimum one, maximum 2563).…”

“…We identified 57 articles analyzing MLH1 promoter methylation [ 19 , 26 , 32 , 33 , 34 , 36 , 40 , 42 , 46 , 47 , 52 , 55 , 57 , 58 , 59 , 69 , 71 , 75 , 79 , 81 , 82 , 83 , 84 , 85 , 86 , 90 , 91 , 94 , 95 , 96 , 99 , 100 , 112 , 113 , 116 , 122 , 124 , 125 , 127 , 128 , 129 , 136 , 137 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 ,…”

“…We identified eight articles which investigated the role of IHC in the theragnostics for MMRd tumors in EC [ 53 , 88 , 93 , 95 , 122 , 136 , 161 , 162 ].…”

“…Immune checkpoint pathways such as PD-1/PD-L1 are the main target for immunotherapy in EC. We identified four articles studying PD-L1 expression in MMRd tumors [ 88 , 95 , 136 , 161 ]. All the articles reported an increase in the expression of PD-L1 ranging from 60.4% to 100% in the peritumoral or tumoral compartment in MMRd tumors.…”

Programmed Cell Death Ligand-1 (PDL-1) Correlates With Tumor Infiltration by Immune Cells and Represents a Promising Target for Immunotherapy in Endometrial Cancer

“…Little is known about the molecular mechanisms of PD-L1 in EC cells. The factor interacts with the protein β-catenin which is responsible for cell motility and malignant signal transduction (26). Furthermore, bioinformatic analyses demonstrated that PD-1/PD-L1 signaling pathways crucially control chemokines and signaling and effector proteins of immune cells (27).…”