Association of glutaminase expression with immune-suppressive tumor microenvironment, clinicopathologic features, and clinical outcomes in endometrial cancer

Objective: Increased glutamine metabolism by cancer cells via upregulation of the drug-targetable enzyme glutaminase may contribute to an immune-suppressive tumor microenvironment. Inhibiting glutamine metabolism can not only suppress tumor growth, but also enhance tumor-specific immunity. We investigated the relationship between glutaminase expression, the immune tumor microenvironment, and clinicopathologic features in endometrial cancer.

Methods: Tissue microarrays constructed from 87 primary endometrial cancer specimens were stained by immunohistochemistry for glutaminase, c-Myc, mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), postmeiotic segregation increased 2 (PMS2), estrogen receptor (ER), progresterone receptor (PR), CD8, FoxP3, CD68, programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). We compared the immune tumor microenvironment and clinicopathologic features between glutaminase-high (H-score≥median) versus glutaminase-low (H-score<median) endometrial cancers. We also evaluated data from The Cancer Genome Atlas (TCGA) for 527 endometrial cancer patients in whom RNA-Seq for glutaminase expression was performed and compared long-term clinical outcomes between glutaminase-high (RNA-Seq Z-score≥median) versus glutaminase-low (RNA-Seq score<median) patients.

Results: In the tissue microarray analysis, glutaminase expression was positively correlated with c-Myc expression (r=0.4226, p<0.0001). Glutaminase-high endometrial cancers were associated with non-endometrioid histology (p=0.0001), high histologic grade (p=0.0004), myometrial invasion (p=0.017), advanced stage (p=0.012), increased FoxP3⁺ regulatory T cells (p=0.008), increased CD68⁺ tumor-associated macrophages (p=0.010), and higher PD-L1 combined positive scores (p=0.043). In the TCGA analysis, glutaminase-high (RNA-Seq Z-score≥median) patients showed worse overall (p=0.004) and progression-free (p=0.032) survival than glutaminase-low (RNA-Seq score<median) patients.

Conclusions: Our findings indicate that increased glutaminase expression is associated with an immune-suppressive tumor microenvironment, poor clinicopathologic features, and worse long-term outcomes in patients with endometrial cancer.