CD58 alterations and their role in regulating antitumor immune responses in diffuse large B-cell lymphoma.

7057 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.