open access publication

Article, 2023

Ibrutinib sensitizes CLL cells to venetoclax by interrupting TLR9-induced CD40 upregulation and protein translation

Leukemia, ISSN 1476-5551, 0887-6924, Volume 37, 6, Pages 1268-1276, 10.1038/s41375-023-01898-w

Contributors

Kielbassa, Karoline [1] [2] [3] Haselager, Marco Vincent 0000-0002-1410-7285 [1] [2] [3] Bax, Danique J C [3] Van Driel, Bianca Francisca [3] Dubois, Julie M N [3] Levin, Mark-David 0000-0003-2139-3547 [4] Kersting, Sabina S [5] Svanberg, Rebecka 0000-0001-7779-8397 [6] Niemann, Carsten Utoft 0000-0001-9880-5242 [6] [7] Kater, Arnon Philip 0000-0003-3190-1891 [1] [2] [3] Eldering, Eric E 0000-0003-0561-6640 (Corresponding author) [1] [2] [3]

Affiliations

  1. [1] Amsterdam Institute for Infection and Immunity, Cancer Immunology, Amsterdam, the Netherlands
    2. [NORA names: Netherlands; Europe, EU; OECD];
  2. [2] Amsterdam UMC Location VUmc
    3. [NORA names: Netherlands; Europe, EU; OECD];
  3. [3] University of Amsterdam
    4. [NORA names: Netherlands; Europe, EU; OECD];
  4. [4] Albert Schweitzer Ziekenhuis
    5. [NORA names: Netherlands; Europe, EU; OECD];
  5. [5] Haga Hospital
    6. [NORA names: Netherlands; Europe, EU; OECD];

Abstract

Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins within the lymph node (LN) microenvironment. Signaling via B-cell receptor, Toll-like receptors and CD40 collectively reduce sensitivity to the BCL-2 inhibitor venetoclax. Time-limited treatment with venetoclax plus the BTK-inhibitor ibrutinib results in deep remissions, but how this combination affects LN-related signaling is not yet completely clear. Therefore, samples obtained from the HOVON141/VISION phase 2 clinical trial were used to analyze this. Two cycles of lead-in ibrutinib monotherapy resulted in decreased protein expression of Bcl-2 proteins in circulating CLL cells. Strikingly, at this timepoint CD40-induced venetoclax resistance was strongly attenuated, as was expression of CD40. Since CD40 signaling occurs within the CLL LN, we tested various LN-related signals that could affect CD40 signaling. While BCR stimulation had only a minor effect, TLR9 stimulation via CpG led to significantly increased CD40 expression and importantly, reverted the effects of ibrutinib treatment on venetoclax sensitivity by inducing overall protein translation. Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.

Keywords

B cell receptor, B cells, BCL-2 inhibitor venetoclax, BCR, BCR stimulation, BTK inhibitor ibrutinib, BTK inhibitors, Bcl-2, Bcl-2 protein, CD40, CD40 expression, CD40 signaling, CD40 upregulation, CLL cells, CpG, LN microenvironment, TLR9, TLR9 stimulation, Toll-like receptors, cells, chronic lymphocytic leukemia, chronic lymphocytic leukemia cells, circulating CLL cells, combination, cycle, decreased protein expression, deep remission, effect, effect of ibrutinib treatment, effects of ibrutinib, expression, expression of Bcl-2 protein, expression of CD40, findings, ibrutinib, ibrutinib monotherapy, ibrutinib treatment, increased CD40 expression, inhibit priming, inhibitor venetoclax, interruption, leukemia, lymph, lymph nodes, lymphocytic leukemia, mechanism, microenvironment, monotherapy, nodes, phase 2 clinical trial, pro-survival proteins, protein, protein translation, receptors, reduced sensitivity, remission, resistance, samples, sensitivity, signal, stimulation, time-limited treatment, translation, treatment, trials, upregulated Bcl-2 protein, upregulation, venetoclax, venetoclax resistance, venetoclax sensitivity

Funders

  • Academic Medical Center

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