CD24 is a surrogate for ‘immune‐cold’ phenotype in aggressive large B‐cell lymphoma

The tumor microenvironment (TME) is a critical regulator of the development of malignant lymphoma. Therapeutics targeting the TME, especially immune checkpoint molecules, are changing the treatment strategy for lymphoma. However, the overall response to these therapeutics for diffuse large B‐cell lymphoma (DLBCL) is modest and new targets of immunotherapy are needed. To find critical immune checkpoint molecules for DLBCL, we explored the prognostic impact of immune checkpoint molecules and their ligands using publicly available datasets of gene expression profiles. In silico analysis of three independent datasets (GSE117556, GSE10846, and GSE181063) revealed that DLBCL expressing CD24 had a poor prognosis and had a high frequency of MYC aberrations. Moreover, gene set enrichment analysis showed that the ‘MYC‐targets‐hallmark’ (false discovery rate [FDR] = 0.024) and ‘inflammatory‐response‐hallmark’ (FDR = 0.001) were enriched in CD24‐high and CD24‐low DLBCL, respectively. In addition, the expression of cell‐specific markers of various immune cells was higher in CD24‐low DLBCL than in CD24‐high DLBCL. CIBERSORT analysis of the datasets showed fewer macrophages in CD24‐high DLBCL than in CD24‐low DLBCL. Additionally, immunohistochemical analysis of 335 cases of DLBCL showed that few TME cells were found in CD24‐high DLBCL, although statistical differences were not observed. These data indicate that CD24 expression suppresses immune cell components of the TME in DLBCL, suggesting that CD24 may be a target for cancer immunotherapy in aggressive large B‐cell lymphoma.