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Targeting the tumor microenvironment in CLL
exhaustion/chronic activation T-cell phenotype illustrated by PD-1 downregulation,33,35 supporting the concept that ibrutinib improves T-cell function. Similarly, treatment with acalabrutinib and zanubrutinib downregulated T-cell PD-1 expresssion.35,40 Thus, reduced exhaustion pheno- types could be due to indirect removal of tumor burden by all three BTK inhibitors. However, improved T-cell func- tionality may also be due to differential effects on CD4+ and CD8+ subsets, which could be linked to direct off-tar- get activity of ibrutinib.
ITK has particular importance for Th2 T-cell polarization as well as for the development of Treg. Ibrutinib promoted Th1 polarization in a CLL mouse model,38 but this has been more challenging to detect in patients receiving therapy.35 Furthermore ex vivo ibrutinib treatment of γδ T cells from CLL patients promoted a Th1 phenotype leading to improved antitumor effector function, indicating effects due to direct off-target ITK inhibition.42 Ibrutinib treat- ment also reduced the fraction of Treg in CLL patients,43 while treatment with acalabrutinib did not affect Treg num- bers, further indicating direct off-target ITK inhibition by ibrutinib.35,43 Reduced numbers of CD4+ IL-17 producing Th cells (Th17 cells) in ibrutinib-treated patients, as well as reduced Th17 differentiation in vitro, have also been demonstrated, recapitulating findings from ITK knockout mice.33 As for Treg, acalabrutinib did not affect Th17-cell numbers.35 However, contradictory findings, with increased Th17 T cells in patients with CLL receiving ibru- tinib, have been reported.35 This is perhaps due to complex CD4+ subset changes which are related to time on therapy and prior treatment history in study cohorts. Additionally, although current data support ibrutinib-mediated direct ITK inhibition in both Th17 and Treg subsets, given their antagonizing roles,44 indirect effects on Th17 T cells due to reductions of Treg may “dominate” the direct effects, and contribute to this compartment expanding.
Inhibition of B-cell receptor signaling leading to redistri- bution of CLL cells from sanctuary niches into the periph- eral blood is a hallmark of ibrutinib treatment,45 the mech- anism of which is, in part, disruption of microenviron- mental interactions. Bone marrow specimens from ibruti- nib-treated patients revealed disruption of (tumor-associ- ated) macrophage-CLL cell contacts, with macrophage cellular protrusions contracting during therapy, likely reflecting a loss of NLC pro-survival signaling.33 Ibrutinib has been shown to block BTK and downstream transcrip- tion factors within macrophages, resulting in downregu- lated expression of the chemokines CXCL12 and CXCL13, thus suggesting a direct effect of ibrutinib on macrophages.46 The reduced levels of these chemokines further compromised adhesion and migration of malig- nant B cells in vitro.46 In accordance, ibrutinib-mediated inhibition of the migratory response of CLL cells towards these chemokines was demonstrated.33,47 Thus, direct effects of ibrutinib on macrophages seem to mediate inhibited CLL-cell chemotaxis and adhesion, thereby like- ly contributing significantly to the clinical reduction in lymph node and spleen size, and concomitant peripheral lymphocytosis.45 Contrariwise, unfavorable effects of ibrutinib, including impaired phagocytosis in macrophages and neutrophils, and inhibited NK-cell acti- vation and suppressed antibody-dependent cellular cyto- toxicity by NK cells have been demonstrated, likely relat- ed to direct inhibition of BTK and ITK by ibrutinib in these cells. This may have important clinical implications
for combination treatment with CD20 antibodies.48 Reduction of MDSC and a concomitant increase in clas- sical monocytes were recently demonstrated in patients with CLL after 12 months of ibrutinib treatment,36 and were likely due to both direct effects of BTK inhibition in MDSC,49 and indirect effects induced through reduced tumor burden. Given their suppressive effect on T-cell function,23 a reduction of MDSC may also further con- tribute indirectly to improved T-cell/immune functions. Moreover, ibrutinib abrogates the adherence of vascular cell adhesion molecule-1-positive CLL cells to fibronectin on stromal cells, thereby further reducing the ability of CLL cells to remain in the protective tissue niches.47,50 Although ibrutinib produces impressive clinical results, treatment resistance is emerging,6 and residual disease remains a challenge. In vitro studies have demonstrated a protective effect of NLC in the presence of ibrutinib, thereby implying a role for NLC in contributing to residual disease and the development of ibrutinib resistance.7 Furthermore, it was demonstrated that ibrutinib-resistant subclones harboring BTK mutations promote proliferation of BTK wild-type cells during ongoing ibrutinib treatment through paracrine stimulation, further implying a role of microenvironment crosstalk in the development of resist-
ance.8
A number of studies seem to point toward improved
clinical immune function due to the TME modulations mediated by ibrutinib.51,52 This issue, however, remains controversial, as there is still a lack of data demonstrating reduced risk of infections compared to prior ibrutinib treatment. However, studies do indicate that restoration of immune phenotypes and function establish after long- term treatment.33,34,36,51 This is in line with previous real- world data demonstrating that infectious adverse events in patients with CLL treated with ibrutinib are most fre- quent during the first 6 months, after which infection rates decline.53 Thus, the long-term indirect effects of ibrutinib due to reduced tumor burden and disrupted CLL-TME crosstalk may allow the various immune cell compart- ments to re-establish normal host immunity; however, further studies on this matter are warranted.
Continued investigation of the impact of BTK inhibitors on the TME compartments is warranted in order to pro- vide tailored treatment strategies to improve clinical out- come (residual and progressive disease) and immune func- tion in patients with CLL, while evading emergence of drug resistance. The most important effects of BTK inhibitors on the TME are summarized in Table 1 and illustrated in Figure 2.
PI3K inhibitors
In addition to BTK, PI3K constitutes another critical component of the B-cell receptor signaling pathway (Figure 2). Idelalisib is a selective inhibitor of PI3Kδ, the PI3K iso- form generally restricted to hematopoietic cell types,54 and was the first PI3K inhibitor approved for CLL treatment. In preclinical studies, idelalisib induced caspase-dependent apoptosis of primary CLL cells and also reduced their chemokine secretion, independently of cytogenetics or IgHV mutational status.55,56 Although treatment of autolo- gous T cells and NK cells with idelalisib does not induce apoptosis in these cells, it does decrease their production of inflammatory cytokines (IL-6, IL-10, tumor necrosis factor-
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