Loss of Ribosomal Protein L22 (RPL22) Expression Identifies a Transcriptional Subset of MLH1-Deficient Endometrial...

Microsatellite instability-high defines one of the major subsets of endometrial cancer (EC), characterized by defects in DNA mismatch repair, most often by loss of MLH1 protein expression, and sensitivity to immunotherapies. RPL22 is selectively mutated in microsatellite instability-high cancers, resulting in loss of protein expression. The significance of this mutation is unknown. An immunohistochemistry assay was developed that reliably detected ECs with ribosomal protein L22 (RPL22) protein loss. With a cohort of ECs, we identified MLH1-deficient cancers with loss of RPL22 expression. Using digital spatial transcriptomics, a subset was identified that was characterized by no expression of RPL22, lower expression of β-2 microglobulin, lack of expression of immune activation pathways, and lower numbers of tumor-associated CD8+ lymphocytes. β-2 Microglobulin, which is necessary for antigen presentation to T lymphocytes, was decreased in EC cell lines with RPL22 knocked down. Neither RPL22 expression nor levels of tumor-associated T lymphocytes were associated with tumor mutation burden or PD-L1 expression, 2 biomarkers that are assessed in patients considered for immunotherapies. This study provides the first evidence that RPL22 deficiency is an easily measured indicator of a unique subset of MLH1-deficient ECs that can be characterized as immune low. Our study suggests that patients with RPL22-deficient tumors could represent poor candidates for CD8+ T-cell-based immunotherapies, a current frontline therapy for MLH1-deficient ECs.