Impact of LAG-3/FGL1 pathway on immune evasive contexture and clinical outcomes in advanced urothelial carcinoma.

Autor:	Yoshida T; Department of Urology and Andrology, Kansai Medical University, Osaka, Japan yoshidtk@takii.kmu.ac.jp.; Graduate School of Engineering, Tottori University, Tottori, Japan.; Department of Urology, Osaka Saiseikai-Noe Hospital, Osaka, Japan.; Corporate Sponsored Research Programs for Multicellular Interactions in Cancer, Kansai Medical University, Osaka, Japan., Nakamoto T; Department of Urology and Andrology, Kansai Medical University, Osaka, Japan.; Department of Pathology, Kansai Medical University, Osaka, Japan., Atsumi N; Corporate Sponsored Research Programs for Multicellular Interactions in Cancer, Kansai Medical University, Osaka, Japan.; Department of Pathology, Kansai Medical University, Osaka, Japan., Ohe C; Department of Urology and Andrology, Kansai Medical University, Osaka, Japan.; Department of Pathology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan., Sano T; Department of Urology and Andrology, Kansai Medical University, Osaka, Japan., Yasukochi Y; Department of Genome Analysis, Institute of Biomedical Science, Kansai Medical University, Osaka, Japan., Tsuta K; Corporate Sponsored Research Programs for Multicellular Interactions in Cancer, Kansai Medical University, Osaka, Japan.; Department of Pathology, Kansai Medical University, Osaka, Japan., Kinoshita H; Department of Urology and Andrology, Kansai Medical University, Osaka, Japan.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Jul 23; Vol. 12 (7). Date of Electronic Publication: 2024 Jul 23.
DOI:	10.1136/jitc-2024-009358
Abstrakt:	Background: Anti-programmed death-1 (PD-1)/anti-PD-ligand-1 (PD-L1) pathway inhibition is a standard regimen for advanced urothelial carcinoma (UC); however, its limited efficacy has been reflected in reported medium response rates. This study explored the role of next-generation coinhibitory receptors (IRs; lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain 3 (TIM-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT)) and their ligands (LGs) in the response to PD-(L)1 blockade therapy and the oncological outcomes in patients with UC. Methods: We investigated metastatic UC cases who underwent PD-(L)1 therapy (cohort 1: n=348, cohort 2: n=89, and cohort 4: n=29) or advanced UC cases involving surgery (cohort 3: n=293 and cohort 5: n=90). We assessed the mRNA expression profiles and corresponding clinical information regarding IRs and LGs using cohorts 1, 2, and 3. Additionally, we elucidated the spatial features of these targeted markers using multiplex immunohistochemistry (mIHC) on formalin-fixed paraffin-embedded samples from cohorts 4 and 5. Survival, differential expressed gene, and Gene Set Enrichment analyses were performed. For mIHC, quantitative analyses were also performed to correlate immune and tumor cell densities with patient survival. Results: LAG-3 expression was strongly associated with the responsiveness of PD-(L)1 blockade compared with the expression of TIM-3 and TIGIT . In tumors with high LAG-3 levels, the increased expression of fibrinogen-like protein 1 ( FGL1 ) had a significantly negative effect on the response to PD-(L)1 blockade and overall survival. Moreover, high FGL1 levels were associated with elevated CD4 + regulatory T-cell gene signatures and the upregulation of CD39 and neuropilin-1 , with both indicating CD8 + T-cell exhaustion. mIHC analyses revealed that patients with stromal CD8 + LAG-3 + cells high -tumor FGL1 + cells high exhibited a significant negative correlation with survival rates compared with those with stromal CD8 + LAG-3 + cells high -tumor FGL1 + cells low . Conclusions: LAG-3 expression and high FGL1 coexpression are important predictive factors of adverse oncological outcomes related to the presence of immunosuppressive contextures. These findings are hypothesis-generating, warranting further mechanistic and clinical studies aimed to evaluate LAG-3/FGL1 blockade in UC. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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