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Bladder cancer intrinsic LRFN2 drives anticancer immunotherapy resistance by attenuating CD8 + T cell infiltration and functional transition.
- Source :
-
Journal for immunotherapy of cancer [J Immunother Cancer] 2023 Oct; Vol. 11 (10). - Publication Year :
- 2023
-
Abstract
- Background: Immune checkpoint inhibitor (ICI) therapy improves the survival of patients with advanced bladder cancer (BLCA); however, its overall effectiveness is limited, and many patients still develop immunotherapy resistance. The leucine-rich repeat and fibronectin type-III domain-containing protein (LRFN) family has previously been implicated in regulating brain dysfunction; however, the mechanisms underlying the effect of LRFN2 on the tumor microenvironment (TME) and immunotherapy remain unclear.<br />Methods: Here we combined bulk RNA sequencing, single-cell RNA sequencing, ProcartaPlex multiple immunoassays, functional experiments, and TissueFAXS panoramic tissue quantification assays to demonstrate that LRFN2 shapes a non-inflammatory TME in BLCA.<br />Results: First, comprehensive multiomics analysis identified LRFN2 as a novel immunosuppressive target specific to BLCA. We found that tumor-intrinsic LRFN2 inhibited the recruitment and functional transition of CD8 <superscript>+</superscript> T cells by reducing the secretion of pro-inflammatory cytokines and chemokines, and this mechanism was verified in vitro and in vivo. LRFN2 restrained antitumor immunity by inhibiting the infiltration, proliferation, and differentiation of CD8 <superscript>+</superscript> T cells in vitro. Furthermore, a spatial exclusivity relationship was observed between LRFN2 <superscript>+</superscript> tumor cells and CD8 <superscript>+</superscript> T cells and cell markers programmed cell death-1 (PD-1) and T cell factor 1 (TCF-1). Preclinically, LRFN2 knockdown significantly enhanced the efficacy of ICI therapy. Clinically, LRFN2 can predict immunotherapy responses in real-world and public immunotherapy cohorts. Our results reveal a new role for LRFN2 in tumor immune evasion by regulating chemokine secretion and inhibiting CD8 <superscript>+</superscript> T-cell recruitment and functional transition.<br />Conclusions: Thus, LRFN2 represents a new target that can be combined with ICIs to provide a potential treatment option for BLCA.<br />Competing Interests: Competing interests: None declared.<br /> (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Details
- Language :
- English
- ISSN :
- 2051-1426
- Volume :
- 11
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal for immunotherapy of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 37802603
- Full Text :
- https://doi.org/10.1136/jitc-2023-007230