Immune signaling in Chronic Lymphocytic Leukemia
(Auto)antigenic stimulation is critical throughout the natural history of Chronic Lymphocytic Leukemia (CLL). CLL exhibits a highly skewed immunoglobulin (IG) gene repertoire, while patient survival is associated with the somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) genes: in particular, those carrying no or few somatic hypermutations (SHM) within their immunoglobulin heavy variable (IGHV) genes (“unmutated”, U-CLL) experience aggressive disease, contrasting those with a heavier SHM load (“mutated”, M-CLL) who follow more indolent disease courses (Damle et al. Blood 1999; Hamblin et al. Blood 1999).
A remarkable phenomenon in CLL is that, contrary to chance, subsets of cases may carry quasi-identical or ‘stereotyped’ B-cell receptors (BcR), in up to 30% of patients (Stamatopoulos et al. Blood 2007; Murray et al. Blood 2008; Darzentas et al. Leukemia 2010), strongly implying that CLL ontogeny is not stochastic but rather driven by interactions between the clonogenic cells and a restricted set of antigenic elements. Recent research suggests that the molecular classification of CLL on the basis of BcR IG primary structures (Agathangelidis et al. Blood 2012) is biologically and clinically relevant (Baliakas et al. Lancet Haematol. 2014; Mansouri et al. J Exp Med 2015; Gounari et al. Blood 2015).
CLL cells with distinct BcR IGs (e.g. U-CLL versus M-CLL or subsets with particular stereotyped BcR IG) exhibit different antigen reactivity (Lanemo-Myhinder et al. Blood 2010; Chu et al. Blood 2010) and differential functional responses to immune stimulation (Lanham et al. Blood 2003; Petlickovski et al. Blood 2005; Mockridge et al. Blood 2007; Longo et al, Leukemia 2007; Muzio et al. Blood 2008; Ntoufa et al. Mol Med 2012; Apollonio et al. Blood 2013; Chatzouli et al. J Immunol 2014).
In more detail, after surface IgM ligation, U-CLL cases exhibit more pronounced responses proximal to the membrane (i.e. Syk phosphorylation and intracellular Ca2+ mobilization compared) to M-CLL cases, who are often unresponsive to this treatment, resembling B cells anergized through the BcR by chronic exposure to autoantigen(s).
The significant differences in responsiveness to BcR crosslinking among cases with similar surface IgM expression levels pose an interesting question and suggest that additional factors may be implicated in shaping the functional outcome of immune signaling in CLL. Support for this notion emerged from studies by various groups including ours showing that CLL cells may also interact with their microenvironment via non-BcR mediated modalities, including CD40 (Scielzo et al. Leukemia 2011), innate immunity receptors such as the Toll like receptors (TLR) (Muzio et al. Br J Haematol 2008; Arvaniti et al. Haematologica 2011; Ntoufa et al. Mol Med 2012), chemokine receptors, complement receptors.
All the aforementioned results become increasingly important in view of recent developments showing that interfering with immune signaling in CLL is feasible and clinically relevant as evidenced by the clinical efficacy of the btk inhibitor Ibrutinib and the PI3Kδ inhibitor idelalisib as single agent or in combination with chemoimmunotherapy (Bendamustine-Rituximab) in both relapsed/refractory and treatment-naïve patients. However, despite the remarkable results obtained with the novel agents, most patients achieve only partial responses with persistent lymphocytosis underscoring the need for further investigations into the underlying immune mechanisms and possible targets for intervention.
Our ongoing and planned research focuses on:
- identifying subset-specific biochemical signaling signatures of predictive value
- understanding microenvironmental interactions and the mechanism(s) of response to signalling inhibitors.