Lymphocyte activation gene-3 is associated with programmed death-ligand 1 and programmed cell death protein 1 in small cell lung cancer

Abstract

Background: In recent years, immunotherapy has achieved notable success in cancer treatment. Indeed, the novel immune checkpoint lymphocyte activation gene-3 (LAG3) has shown promising therapeutic efficacy in non-small cell lung cancer. However, it is unclear about the role of LAG3 in immunotherapy and survival in small cell lung cancer (SCLC). Methods:The expression of LAG3 in SCLC was evaluated in four public datasets. The association of LAG3 with programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), and overall survival (OS) was investigated. The LAG3-related biological processes and pathways were identified by functional analyses.Results: LAG3 expression was detected in SCLC tumor tissues. In the cBioPortal dataset with 81 clinical SCLC samples, LAG3 expression was markedly associated with PD-1 and PD-L1 expression (both P<0.050).In addition, Patients with high LAG3 expression had a trend toward a better OS (P=0.073). A similar survival trend was also observed in the GSE60052 dataset. Significantly, LAG3 expression was related to immunerelated biological processes, such as immune response, antigen processing and presentation, and T cell co-stimulation (all P<0.001).Conclusions: This study demonstrated that LAG3 is an important immune checkpoint that is closely associated with PD-1/PD-L1. LAG3 may be a promising novel immunotherapy target for SCLC.

Orchestrating smart therapeutics to achieve optimal treatment in small cell lung cancer: recent progress and future directions

“…Immunotherapies represent a major advance in the management of SCLC. Several novel targets, which have been discovered due to our deepening understanding of the immunological milieu of SCLC, include TIM-3, TIGIT and LAG3 [ 172 – 174 ], as demonstrated in Fig. 5 A. Sun’s study has revealed the expression of LAG3 in SCLC tumor tissues.…”

“…Significantly, LAG3 expression was linked with immune-associated biological processes including immune response, antigen presentation, and T cell co-stimulation. They demonstrated that LAG3 is a vital immune checkpoint closely related with PD-1/PD-L1[ 174 ]. Therefore, LAG3 holds as an appealing novel immunological target for SCLC.…”

Configuring Therapeutic Aspects of Immune Checkpoints in Lung Cancer

“…The expression of LAG on tumors was established by the TCGA, showing that its expression on various tumors has a direct effect on prognosis. Hui sun et al conducted a study in a cohort of SCLC patients showing the LAG-3 expression in the tumor tissues and its association with PD-1 expression [142]. Thus, the development of a molecule targeting the LAG-3 checkpoint might prove to be efficacious.…”

LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors

“…LAG-3+ TILs are prevalent in two broad histological subtypes of lung cancer: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), which include adenocarcinoma, squamous cell carcinoma and large cell carcinoma [ 53 ]. GSE149507 cohort study revealed that LAG-3 levels were significantly overexpressed in all samples from SCLC patients compared with healthy lung tissues [ 55 ]. Similar tendencies were observed in a study conducted on 53 patients with NSCLC, where intratumoral Treg cells presented higher levels of immunosuppressive molecules, such as LAG-3, CTLA-4 and PD-1 than Tregs from tumor-adjacent tissues or peripheral blood Treg cells [ 56 ].…”

“…In a study conducted by Ma et al LAG-3-expressing CD4+CD25- T cells infiltrated the resected tumors and were more common in metastases than in primary tumors [ 57 ]. Evidence suggests that in lung tumors overexpression of LAG-3, PD-1 and TIM-3 is connected with prominent T cell activation (CD69/CD137), effector function (Granzyme-B), and proliferation (Ki-67), but also with elevated levels of proapoptotic markers (FAS/BIM) [ 55 , 58 ]. An increased number of Treg cells and higher expression of inhibitory molecules may have a crucial role in the anti-tumor immune response in NSCLC patients, which may contribute to tumor immune escape and tumor progression [ 56 ].…”