11\u03b2 hydroxysteroid dehydrogenase 1: a new marker for predicting response to immune-checkpoint blockade therapy in non-small-cell lung carcinoma

Ryoko Saito,Jiro Abe,Hironobu Sasano,Ren Nanamiya,Takuto Abe,Chihiro Inoue,Eisaku Miyauchi,Ikuro Sato,Yasuhiro Miki

doi:10.1038/s41416-020-0837-3

Abstract

BackgroundUnderstanding the status of intratumoural immune microenvironment is necessary to ensure the efficacy of immune-checkpoint (IC) blockade therapy. Cortisol plays pivotal roles in glucocorticoid interactions in the immune system. We examined the correlation between intratumourally synthesised cortisol through 11β hydroxysteroid dehydrogenase (HSD) 1 and the immune microenvironment in non-small-cell lung carcinoma (NSCLC).MethodsWe correlated 11βHSD1 immunoreactivity in 125 cases of NSCLC with the amount of intratumoural immune cells present, and 11βHSD1 immunoreactivity with the efficacy of IC blockade therapy in 18 specimens of NSCLC patients. In vitro studies were performed to validate the immunohistochemical examination.Results11βHSD1 immunoreactivity showed a significant inverse correlation with the number of tumour-infiltrating lymphocytes and CD3- or CD8-positive T cells. 11βHSD1 immunoreactivity tended to be inversely correlated with the clinical efficacy of the IC blockade therapy. In vitro studies revealed that 11βHSD1 promoted the intratumoural synthesis of cortisol. This resulted in a decrease in cytokines and in the inhibition of monocyte migration.ConclusionsOur study is the first report clarifying the inhibitory effects of intratumourally synthesised cortisol through 11βHSD1 on immune cell migration. We propose that the response to IC blockade therapy in NSCLC may be predicted by 11βHSD1.

Highlights

Understanding the status of intratumoural immune microenvironment is necessary to ensure the efficacy of immune-checkpoint (IC) blockade therapy
The correlation between the 11βHSD1, 11βHSD2 and/or GC receptor (GR) and clinicopathological factors of the patients Both 11βHSD1 and 11βHSD2 were detected in the cytoplasm of carcinoma cells, and GR was detected in the nuclei of these cells (Fig. 1a–c)
In this study, we initially demonstrated that 11βHSD1 was involved in the in situ activation of GC, and was significantly and inversely correlated with the number of tumour-infiltrating lymphocytes (TILs) and T cells in non-small-cell lung carcinoma (NSCLC) tissues

Summary

Introduction

Understanding the status of intratumoural immune microenvironment is necessary to ensure the efficacy of immune-checkpoint (IC) blockade therapy. We examined the correlation between intratumourally synthesised cortisol through 11β hydroxysteroid dehydrogenase (HSD) 1 and the immune microenvironment in non-small-cell lung carcinoma (NSCLC). RESULTS: 11βHSD1 immunoreactivity showed a significant inverse correlation with the number of tumour-infiltrating lymphocytes and CD3- or CD8-positive T cells. In vitro studies revealed that 11βHSD1 promoted the intratumoural synthesis of cortisol. This resulted in a decrease in cytokines and in the inhibition of monocyte migration. CONCLUSIONS: Our study is the first report clarifying the inhibitory effects of intratumourally synthesised cortisol through 11βHSD1 on immune cell migration. Immune-checkpoint (IC) blockade therapy has been used for patients with various malignant tumours, including non-small-cell lung carcinoma (NSCLC), and has contributed to substantial improvements in patient prognoses. The direct contact of tumour-infiltrating lymphocytes (TILs), including CD8-positive T cells, with tumour cells has been reported to modulate the effects of IC blockade therapy through the tumour’s suppressive effects.[3,4,5]

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