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Cd58 Alterations Govern Antitumor Immune Responses by Inducing Pdl1 and Ido in Diffuse Large B-Cell Lymphoma Publisher Pubmed



Xu X1 ; Zhang Y1 ; Lu Y1 ; Zhang X2 ; Zhao C3 ; Wang J1, 4 ; Guan Q1, 5 ; Feng Y1 ; Gao M1 ; Yu J1 ; Song Z1 ; Liu X1 ; Golchehre Z6 ; Li L1 Show All Authors
Authors
  1. Xu X1
  2. Zhang Y1
  3. Lu Y1
  4. Zhang X2
  5. Zhao C3
  6. Wang J1, 4
  7. Guan Q1, 5
  8. Feng Y1
  9. Gao M1
  10. Yu J1
  11. Song Z1
  12. Liu X1
  13. Golchehre Z6
  14. Li L1
  15. Ren W7
  16. Panhammarstrom Q7
  17. Zhang H1, 8
  18. Wang X1, 8

Source: Cancer Research Published:2024


Abstract

Recurrent abnormalities in immune surveillance–related genes affect the progression of diffuse large B-cell lymphoma (DLBCL) and modulate the response to therapeutic interventions. CD58 interacts with the CD2 receptor on T cells and NK cells and is recurrently mutated and deleted in DLBCL, suggesting that it may play a role in regulating antitumor immunity. In this study, we comprehensively analyzed the genomic characteristics of CD58 through targeted next-generation sequencing, RNA sequencing (RNA-seq), whole-exome sequencing, and single-cell RNA-seq in patients with newly diagnosed DLBCL. The CD58 mutation rate was 9.1%, and the copy number loss rate was 44.7% among all enrolled patients with DLBCL. Notably, CD58 genetic alterations, along with low CD58 expression, significantly correlated with reduced rates of response to R-CHOP therapy and inferior progression-free survival and overall survival. Single-cell RNA-seq revealed that CD58 expression in tumor cells was negatively correlated with CD8+ T-cell exhaustion/dysfunction status. Insufficient T-cell activation resulting from CD58 alterations could not be attributed solely to CD2 signaling. CD58 inhibited the activity of the JAK2/STAT1 pathway by activating the LYN/CD22/SH2 domain–containing phosphatase 1 (SHP1) axis, thereby limiting PDL1 and IDO expression. Elevated PDL1 and IDO expression in CD58-deficient DLBCL cells led to immune evasion and tumor-intrinsic resistance to chimeric antigen receptor T-cell therapy. Direct activation of CD58–CD2 costimulatory signaling in combination with anti-PDL1 blockade or IDO inhibitor sensitized CD58-deficient DLBCL to chimeric antigen receptor T-cell therapy. Collectively, this work identified the multiple roles of CD58 in regulating antitumor immune responses in DLBCL. ©2024 American Association for Cancer Research.
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