Distinct Innate Immunity Pathways to Activation and Tolerance in Subgroups of Chronic Lymphocytic Leukemia with Distinct Immunoglobulin Receptors

Stavroula Ntoufa,Anna Vardi,Vassiliki Aleporou-Marinou,Nikos Papakonstantinou,Chrysoula Belessi,Achilles Anagnostopoulos,Paolo Ghia,Marta Muzio,Kostas Stamatopoulos,Federico Caligaris-Cappio

doi:10.2119/molmed.2011.00480

Abstract

Subgroups of patients with chronic lymphocytic leukemia (CLL) have distinct expression profiles of Toll-like receptor (TLR) pathway-associated genes. To test the hypothesis that signaling through innate immunity receptors may influence the behavior of the malignant clone, we investigated the functional response triggered by the stimulation of TLRs and NOD2 in 67 CLL cases assigned to different subgroups on the basis of immunoglobulin heavy variable (IGHV ) gene usage, IGHV gene mutational status or B-cell receptor (BcR) stereotypy. Differences in the induction of costimulatory molecules and/or apoptosis were observed in mutated versus unmutated CLL. Different responses were also identified in subsets with stereotyped BcRs, underscoring the idea that "subset-biased" innate immunity responses may occur independently of mutational status. Additionally, differential modulation of kinase activities was induced by TLR stimulation of different CLL subgroups, revealing a TLR7-tolerant state for cases belonging to stereotyped subset #4. The distinct patterns of TLR/NOD2 functional activity in cells from CLL subgroups defined by the molecular features of the clonotypic BcRs might prove relevant for elucidating the immune mechanisms underlying CLL natural history and for defining subgroups of patients who might benefit from treatment with specific TLR ligands.

Highlights

In recent years, chronic lymphocytic leukemia (CLL) has emerged as a prototype of cancers in which both genetic and microenvironmental factors concur in the onset, expansion and progression of the disease [1]
We confirmed and significantly extended our previously reported findings [31], showing that: (i) TLR1/2, TLR2/6, TLR9 and NOD2 were functional in the great majority of cases, albeit in a heterogeneous fashion; (ii) TLR4, previously shown to be expressed at very low levels in a minority of CLL cases [32], was unresponsive to stimulation with LPS; and (iii) TLR8, showing high protein expression in most CLL cases [31], was unresponsive to stimulation with ORN 08 (Figure 1)
In conclusion, we demonstrate that the biological behavior of CLL malignant B cells can be influenced by signals triggered by innate immunity receptors

Summary

Introduction

Chronic lymphocytic leukemia (CLL) has emerged as a prototype of cancers in which both genetic and microenvironmental factors concur in the onset, expansion and progression of the disease [1]. Antigenic stimulation through the B-cell receptor (BcR) seems to be critically involved in CLL development and evolution as evidenced by: (i) restrictions in the immunoglobulin heavy variable (IGHV) gene repertoire [1,2,3,4,5,6,7]; (ii) different prognosis of patients with different IGHV gene mutational status [8,9,10]; and (iii) the existence of subsets of patients sharing BcRs with restricted, quasi-identical Ig sequences (stereotyped BcRs) [1,3,4,5,11] in roughly 30% of cases Taken together, all these observations indicate that a correspondingly restricted set of antigens or structurally related epitopes might be impli-. The NLR family (nucleotide-binding domain, leucine-rich repeat containing), including the NOD1 and NOD2 receptors, constitutes another important class of PRRs with various

Methods

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Discussion

Conclusion