High expression of CD40 on B-cell precursor acute lymphoblastic leukemia blasts is an independent risk factor associated with improved survival and enhanced capacity to up-regulate the death receptor CD95

Abstract

CD40 and CD27, members of the tumor necrosis factor receptor (TNFR) family, are critical regulators of lymphocyte growth and differentiation. In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we prospectively assessed the impact of CD40 and CD27 on outcome in 121 children treated according to the CoALL06-97 protocol. Expression of both CD40 and CD27 was found to be significantly higher in low-than in high-risk patients as defined by standard clinical risk parameters such as age and white blood cell count. In addition, in multivariable analysis, a very high percentage of CD40 ؉ blasts at diagnosis was identified as an independent favorable prognostic factor for relapse-free survival. Of note, high CD40 expression particularly protected against late relapse. In B cells, CD40 is known to enhance both antigenpresenting capacity and sensitivity to proapoptotic signals. Yet, although CD40 ligation does result in significant upregulation of CD80/CD86 in our cohort, it is up-regulation of the death receptor CD95 that significantly correlates with the percentage of CD40 ؉ blasts. Thus very high expression of CD40 on BCP-ALL blasts is an independent prognostic marker indicative of superior relapse-free survival that may in part be due to CD40-dependent death receptor up-regulation. IntroductionAlthough the overall prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is good, identification of new prognostic factors may result in improved risk classification and treatment outcome. Long-term survival is critically influenced by blast sensitivity toward chemotherapeutic agents. Immunologic control mechanisms are also thought to play a role. [1][2][3] In normal B cells, homeostasis is maintained by an intricate regulatory network with the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor/ ligand family of proteins playing a pivotal role in T cell/B cell interactions. [4][5][6][7][8] As adequate stimulation of effector cells as well as susceptibility of the target cells to apoptotic signals are required for optimal immunologic control, the capacity of B cells to respond to CD40 ligand (CD40L) stimulation is critical. In normal B cells, activation via the CD40 receptor promotes differentiation and results in increased expression of costimulatory molecules and the CD95 death receptor, another member of the TNF receptor (TNFR) family. 7,9-11 To various degrees, the CD40 receptor is also expressed on acute lymphoblastic leukemia (ALL) of the B-cell lineage. 12 In analogy to mature B cells, activation via CD40 turns leukemic blasts into efficient antigen-presenting cells mediated by up-regulation of MHC, adhesion, and costimulatory molecules. [13][14][15][16][17] In addition to promoting their antigenpresenting ability, in chronic lymphoblastic leukemia (CLL) it has been shown that CD40 ligation also induces CD95 expression, 18,19 although little is known about CD40-dependent CD95 modulation in BCP-ALL. CD27, another member of the TNF receptor family, also plays an important role in lymphoid di...

Multi-Omics Analysis of Acute Lymphoblastic Leukemia Identified the Methylation and Expression Differences Between BCP-ALL and T-ALL

“…CD40 is the member of the tumor necrosis factor receptor (TNFR) family, are critical regulators of lymphocyte growth and differentiation. Troeger et al (2008) confirmed that the high expression of CD40 in BCP-ALL cells is an independent prognostic indicator, which indicates a better recurrencefree survival.…”

Expression of Immune System-Related Membrane Receptors CD40, RANK, BAFFR and LTβR is Associated with Clinical Outcome of Operated Non-Small-Cell Lung Cancer Patients

“…Findings on CD40 are consistent with the results published by Keidai et al, in which 51.9% of NSCLC tissue specimens [24] and 78% of lung cancer cell lines (14 of 18) expressed CD40 [25]. Furthermore, the expression of CD40 has been documented in many other carcinomas, such as melanomas [26], hepatocellular carcinomas [27] thyroid [28], bladder [29], colon [30], esophageal squamous cell [31], ovarian [32], gastric [33], cervical [34], breast and pancreatic cancer [35], as well as in the vast majority of hematological malignancies [36,37].…”

Highlights of the First International “Immunotherapy in Pediatric Oncology: Progress and Challenges” Meeting

“…Dagmar Dilloo (Heinrich Heine Univ., Germany) presented approaches to enhance GVL in ALL. She has demonstrated that modulation of the ALL blast can also be used to augment GVL, and improved immunogenecity is seen after CD40 activation, via CD70 and CD80/86 upregulation, resulting in substantial T cell priming(51, 52). As blockade of CD70 prevents effector T cell expansion and reduces cytotoxicity, strategies facilitating upregulation of CD70 on antigen-presenting cells are critical for augmenting the quality of an anti-leukemic response against ALL.…”