Stromal LAG-3⁺cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture

Abstract

BackgroundLymphocyte activation gene 3 (LAG-3) is a promising immune checkpoint therapeutic target being evaluated in clinical trials. We assessed the LAG-3+cells distribution, its association with clinical outcomes and immune contexture and its role in the landscape of muscle-invasive bladder cancer (MIBC) treatment.Methods141 patients with MIBC from Zhongshan Hospital were included for survival and adjuvant chemotherapy (ACT) benefit analyses. 32 fresh resected samples of MIBC were collected to detect CD8+T cells functional state. The molecular classification analyses were based on 391 patients with MIBC from The Cancer Genome Atlas. Immunohistochemistry and flow cytometry were performed to characterize various immune cells infiltration.ResultsIn Kaplan-Meier analyses and Cox regression models, stromal LAG-3+cells enrichment was consistently associated with inferior overall survival and disease-free survival, and indicated suboptimal responsiveness to ACT. Patents with high stromal LAG-3+cells possessed increased protumor cells, immunosuppressive cytokines and immune checkpoint expression. The phenotypic analyses of CD8+T cells correlated its dysfunctional state with LAG-3+cells. Besides, LAG-3 mRNA level was linked to luminal and basal subtypes of MIBC. LAG-3-high tumors exhibited limited FGFR3 mutation and signaling signature, and displayed activated immunotherapeutic and EGFR-associated pathway.ConclusionsStromal LAG-3+cells abundance indicated an immunoevasive contexture with dysfunctional CD8+T cells, and represented an independent predictor for adverse survival outcome and ACT resistance in MIBC. LAG-3 expression could potentially be a novel biomarker for FGFR3-targeted and EGFR-targeted therapies and immunotherapy. The crucial role of LAG-3+cells in the therapeutic landscape of MIBC needs further validation retrospectively and prospectively.

The Next-Generation Immune Checkpoint LAG-3 and Its Therapeutic Potential in Oncology: Third Time’s a Charm

“…Consequently, the presence of LAG-3 on tumor-infiltrating immune cells has been described to be associated with poor prognosis and tumor progression. Individual studies reported this observation for various tumor types, including renal cell carcinoma [ 68 ], gastric cancer [ 69 ], bladder cancer [ 70 ], colorectal cancer [ 71 ], chronic lymphocytic leukemia [ 72 ], acute myeloid leukemia [ 73 ], follicular lymphoma [ 74 ], hepatocellular carcinoma [ 75 , 76 ], NSCLC [ 58 ], head and neck squamous cell carcinoma [ 77 ], esophageal squamous cell carcinoma [ 78 ], and diffuse large B cell lymphoma [ 79 ]. These studies suggested a contribution of LAG-3 to immune escape by the tumor, similarly to PD-1.…”

Construction of an Immune-Associated Gene-Based Signature in Muscle-Invasive Bladder Cancer

“…Due to the profound research on the mechanism of tumor immune escape and immunotherapy, IAGs are getting increasing attention in recent years. Current studies had shown the important role of IAGs in various cancers, including MIBC [ 18 – 21 ]. Therefore, IAGs are novel biomarkers, which can predict the survival outcomes and the immune status of MIBC patients.…”

“…Therefore, MIBC patients with a basal molecular type may indicate high-risk scores and poor survival outcomes. Previous studies also demonstrated that the expression of IAGs, such as LAG3, PD-L1, CD3, and IL22, was closely related to the prognosis of different subtypes of MIBC [ 21 – 23 ]. Furthermore, a prognostic nomogram integrated with the IAG signature risk score and clinicopathologic features was established, which could superiorly monitor the prognosis of MIBC patients.…”

Prognostic value of immune-related genes and comparative analysis of immune cell infiltration in lung adenocarcinoma of different genders

“…Recent studies have shown that components in TME, including immune cells, endothelial cells, mesenchymal cells, in ammatory mediators and extracellular matrix, are closely related to the occurrence, progression and prognosis of cancer [4][5][6][7][8][9]. As the two main components, TIICs and stromal cells are regarded as valuable for the effect of tumor immunotherapy [10][11][12][13][14]. It is reported that immune cells, such as T and B cells, macrophages, dendritic cells, monocytes, etc., interact with tumor cells and are correlated to tumor cell proliferation, metastasis and prognosis [15][16][17].…”