This case indicates the potential existence of an endometrial cancer subtype that is sensitive to immune checkpoint blockade based on mechanisms other than those driven by MMR deficiency or PD-L1 positivity.
PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53% and stromal GBP5 in 71%.MMR-deficiency was found in 22%.
On the basis of multivariate logistic regression analysis, CD274 positivity was significantly associated with poorly differentiated histotype (OR: 3.32; 95% CI: 1.46-7.51; P=0.004), MMR deficiency (OR: 10.0; 95% CI: 4.66-21.5; P<0.001), and 'stem-like' immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity (OR: 5.51; 95% CI: 1.66-18.3; P=0.005).
A higher prevalence of PD-L1-positive cases was observed among esophageal specimens compared with gastric ones (p = 0.0003), in high-grade and adenocarcinoma samples in comparison with low-grade dysplasia (p < 0.0001), and in lesions with mismatch repair deficiency (p = 0.028).
This review focuses on the recent development of biomarkers for assessing the efficacy of anti-PD1 antibodies using routine blood tests such as the neutrophil-to-lymphocyte ratio, eosinophil ratio, serum markers such as lactate dehydrogenase, programmed cell death ligand 1 (PD-L1) expression on melanoma cells, microsatellite instability and mismatch repair deficiency assays, as well as soluble CD163, and tumor-associated macrophage-related chemokines (e.g., CXCL5, CXCL10).
There is a biological rationale to evaluate immune-checkpoint inhibitors in refractory GCCs, as PD-L1 is often expressed and refractory tumors often display mismatch repair deficiency or microsatellite instability.
A positive association was identified for PD-L1 expression with mismatch repair deficiency and EBV status; however, no association was revealed with HER2 status.
Low GMS was a manifestation of better prognosis and inflammatory tumor microenvironment, which was related to MMR deficiency (P = 0.042) and EBV infection (P = 0.032), and within this microenvironment, expression of PD-L1 in carcinoma cells (P = 0.030) or in inflammatory cells (P = 0.029) was significantly higher.
PD-L1 expression was more frequently observed in the elderly (TCs P = 0.002), in males (TCs P = 0.029; TIICs P = 0.043), in patients with poorly differentiated adenocarcinoma with solid-type histological features (TCs P < 0.001; TIICs P < 0.001), in patients with MMR deficiency (TCs P < 0.001; TIICs P < 0.001), and in patients with EBV positivity (TCs P = 0.001; TIICs P = 0.050).
However, the prognostic value of PD-L1 expression and the systemic inflammatory response for patients with MMR deficiency has not been fully investigated.
Tumor lymphocytic infiltration (TIL) and programed cell death ligand-1 (PD-L1) have been associated with prognosis in different malignancies while DNA mismatch-repair deficiency (MMR-D) has been associated with response to check-point inhibitors.
Pembrolizumab has been approved for relapsed cervical cancer with programmed death ligand 1 positivity and relapsed solid tumors with mismatch repair deficiency, which applies to 30% of endometrial cancers.
Two key biologically important predictive tissue biomarkers, specifically, PD-L1 and mismatch repair deficiency, have been FDA-approved in conjunction with the checkpoint inhibitor, pembrolizumab.
Although recent literature has been flooded with studies on ICI predictive biomarkers, available data show that currently approved companion diagnostics either leave out many possible responders, as in the case of PD-L1 testing for first-line metastatic lung cancer, or apply to a small subset of patients, such as the recently approved treatment for microsatellite instability-high or mismatch repair deficiency tumors.
These data suggest that MMR deficiency may be a better predictor of response to PD-1/PD-L1 inhibitor therapy than tumor grade in EC, and that potential benefit may vary based on the molecular mechanism of MMR defects.
PD-L1 is expressed in a significant proportion of EC and is associated with mismatch repair deficiency, potentially representing a mechanism of tumor immune evasion and a therapeutic target in EC.