Abstract 775P
Background
Recurrent abnormalities of immune surveillance-related genes play a crucial role in DLBCL progression. Prior studies have shown that CD58, a key adhesion molecule that acts as a ligand for the T-cell costimulatory molecule CD2, is frequently mutated or deleted in certain hematological malignancies. Downregulation or loss of CD58 is linked to resistance to ICB therapy in melanoma and CAR-T therapy in B-cell malignancies. Nevertheless, the role of CD58 in cancer is not yet well understood.
Methods
Comprehensive analysis of the genetic characteristics of CD58 were performed through targeted deep sequencing (n=176), whole exome sequencing (n=38), and RNA-sequencing (n=162) in patients with de novo DLBCL. To investigate the mechanistic impacts of CD58 alterations on co-inhibitory molecules expression and immune cell function, we performed bulk and single-cell RNA-sequencing analysis of tumor samples and conducted co-IP, flow cytometry and co-culture assays in vitro.
Results
We identified that CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled DLBCL patients. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free and overall survival. Single-cell RNA sequencing revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T cell exhaustion/dysfunction status. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the Lyn/CD22/SHP1 axis, thereby limiting PD-L1 and IDO expression. Elevated PD-L1 and IDO expression in CD58 deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to CAR T-cell therapy. Direct activation of CD58-CD2 costimulatory signaling in combination with anti-PD-L1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to CAR T-cell therapy.
Conclusions
Our study comprehensively characterized CD58 genetic alterations in DLBCL. We demonstrated that CD58 downregulation or mutation led to upregulation of PD-L1 and IDO expression mainly by regulating the LYN/CD22/SHP1 axis. Our findings provide novel insights for individualized therapy for DLBCL patients with CD58 mutation or deletion.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.