High gene expression of estrogen and progesterone receptors is associated with decreased t cell infiltration in patients with NSCLC

Abstract

Objectives: Prior studies have demonstrated that signaling via the estrogen and progesterone receptors (ER and PR) may affect prognosis in non-small cell lung cancer (NSCLC). The precise impact of hormone signaling on clinical outcomes in NSCLC, especially in the context of immune checkpoint blockade, remains unclear.

Materials and methods: We obtained RNA-Seq data from The Cancer Genome Atlas (TCGA) to determine mRNA expression levels of ESR1 (ER-α), ESR2 (ER-β), PGR (PR), CYP19A1 (aromatase), and immune-related genes. Tumor infiltration by activated T cells was predicted based on expression of immune metagenes.

Results: High levels of both ESR1 and PGR were associated with significantly decreased tumor infiltration by CD4+ and CD8+ activated T cells. CYP19A1 expression was associated with decreased CD4+ but not CD8+ T cell infiltration. There were no significant differences based on ESR2. These findings persisted after stratifying patients based on sex and tumor histology. In addition, increased ESR1 was associated with high gene expression of immune checkpoint markers, while increased PGR was associated with high levels of TGF-β genes. In a multivariate logistic regression analysis, ESR1, PGR, TGFB1, and the total number of somatic variants were identified as independent factors predicting T cell infiltration.

Conclusions: Increased gene expression of ER-α and PR was associated with decreased activated T cell infiltration in patients with NSCLC. The relevance of hormone receptor status should be validated clinically, including in the context of immune checkpoint inhibitors.

Keywords: Estrogen receptor; Immune checkpoint; Lung cancer; Progesterone receptor; Tumor-infiltrating lymphocytes.