The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy.

Long Long,Honglei Chen,Pronnaphat Phiphatwatchara,Yuyang Zeng,Fuchun Chen,Qi Pan,Xue Zhang

doi:10.18632/genesandcancer.180

Long Long, Honglei Chen + Show 5 more

Open Access

https://doi.org/10.18632/genesandcancer.180

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Abstract

Cancer immunotherapy and tumor microenvironment have been at the forefront of research over the past decades. Targeting immune checkpoints especially programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) has made a breakthrough in treating advanced malignancies. However, the low response rate brings a daunting challenge, changing the focus to dig deeply into the tumor microenvironment for alternative therapeutic targets. Strikingly, the inhibitory immune checkpoint lymphocyte activation gene-3 (LAG-3) holds considerable potential. LAG-3 suppresses T cells activation and cytokines secretion, thereby ensuring immune homeostasis. It exerts differential inhibitory impacts on various types of lymphocytes and shows a remarkable synergy with PD-1 to inhibit immune responses. Targeting LAG-3 immunotherapy is moving forward in active clinical trials, and combination immunotherapy of anti-LAG-3 and anti-PD-1 has shown exciting efficacy in fighting PD-1 resistance. Herein, we shed light on the significance of LAG-3 in the tumor microenvironment, highlight its role to regulate different lymphocytes, interplay with other immune checkpoints especially PD-1, and emphasize new advances in LAG-3-targeted immunotherapy.

Highlights

Over the past decades, the extraordinary advances in cancer immunotherapy have opened a new era for tumor microenvironment (TME)
We provide a detailed description of the significance of the promising immune checkpoint LAG3 in the tumor microenvironment, discuss its role on different types of lymphocytes and autoimmune disorders, highlight its interplay with other immune checkpoints, as well as outline the new advances targeting lymphocyte activation gene-3 (LAG-3) in cancer immunotherapy
Cancer immunotherapy and tumor microenvironment have been at the forefront of cancer research over the past several decades

Summary

INTRODUCTION

The extraordinary advances in cancer immunotherapy have opened a new era for tumor microenvironment (TME). LAG-3-expressing Tregs may utilize an immune tyrosinebased activation motif (ITAM)-modulated suppressive signaling pathway, containing FcγRγ and ERK-modulated recruitment of SHP-1, to indirectly inhibit the function of DCs [33]. Increasing evidence has clarified that the specific KIEELE motif in the cytoplasmic tail is indispensable for abrogating effector CD4+ T cells [52] It can mediate intracellular downstream signal transduction, prevent the entry of T cells into the growth phase of the cell cycle, and depletion of this region is ineffective to negatively regulate T cell function in vitro or in vivo [52]. LAG-3/MHC-II interaction, KIEELE motif, gamma-chain cytokines (IL-2, IL-7, IL-12 and IFN-γ), and Tregs Co-inhibitory molecules especially PD-1, LSECtin and galectin-3. October 11, 2019 *The response rates triple in LAG-3 positive melanoma patients (LAG-3 expression ≥1%). *A safety profile similar to nivolumab monotherapy

A1: BMS 986016

Findings

CONCLUSION AND PERSPECTIVES