Page 28 - 2021_09-Haematologica-web

R. Svanberg et al.
α [TNF-α], interferon [IFN]-γ) and activation-induced mol- ecules (CD40L).55 These changes could potentially have effects on both pro-tumor and antitumor immune func- tions. In addition, idelalisib antagonizes the CLL pro-sur- vival functions of TNF-α and CD40L.55 The effect of idelal- isib on the Treg subset has been a focus of previous studies, as inactivation of PI3Kδ in mice impaired Treg-mediated immune tolerance, enhancing CD8+ T-cell mediated cyto- toxic responses towards tumor cells.57 Interestingly, PI3Kδ inhibition in a CLL mouse model resulted in reduced num- bers and maturation of Tregs; however, this did not result in enhanced antitumor CD8+ T-cell function, likely due to concomitant direct inhibition of PI3Kδ downstream of T- cell receptor signaling.58
Similar to the effects of ibrutinib, idelalisib seems to
interfere with CXCL12-mediated chemotaxis, and abro- gates adhesion of CLL cells to stromal cells, suggesting an indirect mechanism through disrupting the protection of CLL cells provided by the TME.9,56 This correlates with clinical findings of reduced lymphadenopathy and splenomegaly concomitant with lymphocytosis and sig- nificantly reduced levels of CLL-related chemokines.59 It has been demonstrated that idelalisib impairs neutrophil function ex vivo,60 which together with changes in cytotox- ic T-cell subsets and strong suppression of Treg, likely con- tribute to the increased immune-related adverse events and increased risk of infections observed upon idelalisib treatment in clinical trials.61 The next-generation PI3K inhibitor, duvelisib, a dual inhibitor of PI3K isoforms δ and γ, was recently approved for the treatment of
Table 1. Effect of novel therapeutic agents on the microenvironment in chronic lymphocytic leukemia.
Population
T cells
Agent
BTK inhibitors -ibrutinib (ibr) -acalabrutinib (aca) -zanubrutinib (zan)
PI3K inhibitors -idelalisib (id) -duvelisib (duv)
BCL-2 inhibitors -venetoclax (ven)
IMiD/CELMoD -lenalidomide (len) -avadomide (ava)
BTK inhibitors -ibrutinib (ibr)
PI3K inhibitors -idelalisib (id)
IMiD
-lenalidomide (len)
BTK inhibitors -ibrutinib (ibr)
PI3K-inhibitors -idelalisib (id)
BTK inhibitors -ibrutinib (ibr)
PI3K inhibitors -idelalisib (id)
BCL-2 inhibitors
-venetoclax (ven)
Functional changes
Increased T-cell receptor diversity34,37 (ibr)
Enhanced T-cell lytic immune synapse function52 (ibr) Skewing towards T 1 polarization23,53,54 (ibr)
h
Reduced T-cell PD-1 expression/exhaustion phenotype49,51,67 (ibr, aca, zan)
Reduced number of T 51,55 (ibr) reg
Reduced secretion of inflammatory cytokines70 (id)
Inhibition of T functions73,79 (id, duv) reg
Reduced number of T cells70 (ven)
Reduced number of T 70 (ven) reg
Decreased T-cell PD-1 expression70 (ven)
Immune activation, repaired T-cell dysfunction20,24,90,91 (len) Suppressed T-cell proliferation93 (len) PromotionofT1polarization92 (len)
Myeloid cells
Stromal cells
NK cells
Abrogation of the protective contact49 (ibr)
Inhibited chemokine signaling and mediation of CLL cell homing58,59 (ibr) Impaired phagocytosis by macrophages and neutrophils48 (ibr)
Reduced number of MDSC and increased classical monocytes36 (ibr)
Impaired neutrophil inflammatory responses76 (id)
Impaired migration/chemotaxis, abrogated CLL cell protective capability, increased phagocytosis93 (len)
Revoked adherence to stromal cells in protective niches59,60 (ibr) Reduced chemotaxis and impaired adhesion71,74 (id)
Inhibited NK-cell activation48 (ibr) Suppressed ADCC48 (ibr)
Reduced secretion of inflammatory cytokines70 (id)
Decreased number of NK cells70
Improved NK-cell function70
h
Induction of inflammatory IFN type I and II signaling in previously exhausted T-cells27 (ava)
CLL: chronic lymphocytic leukemia; BTK: Bruton tyrosine kinase; ITK; interleukin-2-inducible T-cell kinase; BCL-2: B-cell lymphoma 2; Th: T helper; PD-1: programmed cell death protein 1;Treg: regulatory T-cell; PI3K: phosphoinositide 3’-kinase; IMiD: immunomodulatory drugs; CELMoD: cereblon E3 ligase modulators; IFN: interferon; MDSC: myeloid derived suppressor cells; ADCC: antibody-dependent cellular cytotoxicity.
2316
haematologica | 2021; 106(9)