Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway

Abstract

Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.

PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production

“…Reduced PD-1 expression with STAT3 inhibition was noted on these cells, as well as reduced PD-L1 expression on CLL cells, after treatment with the STAT3 inhibitor ibrutinib. It was also notable that ibrutinib only affected the PD-1 pathway and not other checkpoint inhibitors (35). We noted PD-1 regulation of STAT3 in sarcoidosis CD4 + T cells.…”

The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

“…7 Moreover, ibrutinib has been found to help restore host immunity by increasing T cell number and repertoire diversity, improving T cell function, suppressing immunosuppressive molecule ligands such as programmed death-ligand 1 (PD-L1) on cancer cells, and eliminating BTK-expressed myeloid-derived suppressor cells (MDSC). [8][9][10][11][12][13][14] However, ibrutinib also cast negative effects on anti-tumor immunity through promotion of the anti-apoptosis effect of nurse-like cells (NLCs) and inhibition of NLC phagocytic ability by compelling them expressing M2-skewed tumor associated macrophages phenotype. 15 Besides, ibrutinib has been reported to attenuate rituximab-dependent cytotoxicity by targeting ITK in NK cells.…”

AreBTKandPLCG2mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia?

“…Ibrutinib cause downregulation of the PD-1 exhaustion marker on CD4+ and CD8+ T cells as well as downregulation of the concomitant ligand PD-L1 on neoplastic B cells [24]. Through nonspecific inhibition of ITK, ibrutinib alters differentiation of T cell subsets, skews T cells from a Th2-dominant to a Th1 and CD8+ cytotoxic population [25], and blocks the secretion of cytokines from activated T cells [17].…”