STK11/LKB1 Modulation of the Immune Response in Lung Cancer: From Biology to Therapeutic Impact.

Elvire Pons-Tostivint,Alexandre Lugat,Jaafar Bennouna,Marc Guillaume Denis,Jean-François Fontenau

doi:10.3390/cells10113129

Abstract

The STK11/LKB1 gene codes for liver kinase B1 (STK11/LKB1), a highly conserved serine/threonine kinase involved in many energy-related cellular processes. The canonical tumor-suppressive role for STK11/LKB1 involves the activation of AMPK-related kinases, a master regulator of cell survival during stress conditions. In pre-clinical models, inactivation of STK11/LKB1 leads to the progression of lung cancer with the acquisition of metastatic properties. Moreover, preclinical and clinical data have shown that inactivation of STK11/LKB1 is associated with an inert tumor immune microenvironment, with a reduced density of infiltrating cytotoxic CD8+ T lymphocytes, a lower expression of PD-(L)1, and a neutrophil-enriched tumor microenvironment. In this review, we first describe the biological function of STK11/LKB1 and the role of its inactivation in cancer cells. We report descriptive epidemiology, co-occurring genomic alterations, and prognostic impact for lung cancer patients. Finally, we discuss recent data based on pre-clinical models and lung cancer cohorts analyzing the results of STK11/LKB1 alterations on the immune system and response or resistance to immune checkpoint inhibitors.

Highlights

Germinal heterozygous mutations in the serine/threonine kinase 11 (STK11) gene were first identified as the causal mutation of the Peutz-Jeghers Syndrome, an autosomal dominant condition characterized by multiple hamartomatous polyps in the gastrointestinal tract and an increased cancer risk [1]
The STK11 gene codes for liver kinase B1 (LKB1), a highly conserved serine/threonine kinase that acts as a sensor of cellular energy, giving it a special role in cellular metabolism, especially in cancer cells [2]
This review aims to provide an overview of STK11/LKB1 biological and its view aims to provide overview of STK11/LKB1 biological andthe its relevance implications in carcinogenesis

Summary

Introduction

Germinal heterozygous mutations in the serine/threonine kinase 11 (STK11) gene were first identified as the causal mutation of the Peutz-Jeghers Syndrome, an autosomal dominant condition characterized by multiple hamartomatous polyps in the gastrointestinal tract and an increased cancer risk [1]. AMPK is involved in multiple metabolic pathways to increase ATP production and to stop ATP consumption switching metabolism from an anabolic state to a catabolic state This pathway promotes cell survival under stress conditions but impairs cell growth and proliferation. STK11/LKB1 reschedules cell metabolism by restraining the activity of anabolic enzymes and by promoting the production of instantly available energy with ATP, slowing down cell growth and ATPconsuming processes. It protects the genome from ROS-induced oxidation by regulating antioxidant gene products, and promotes cell survival under stress conditions.

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