The Lymphoma Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

iwCLL 2017 | Ibrutinib inhibits IL-4 production by T-cells and expression of smIL-4R on CLL B-cells 

May 16, 2017

The second session at this year’s iwCLLwas titled “Role of Non-Leukemic Cells and the Microenvironment in CLL Development”, and was jointly chaired by Silvia Deaglio( University of Turin, Torino, Italy) and Christopher Pepper( Cardiff University, Wales, UK).

Shih-Shih Chenfrom the Feinstein Institute for Medical Research, Manhasset, New York, USA, gave a talk during this session called “IL-4R – IL-4 axis Disruption by Ibrutinib Therapy Contributes to the Greater Vulnerability of U-CLL Clones to Loss of Microenvironmental Inputs.”

IL-4 is a crucial factor in the microenvironment and is associated with CLL progression. It reduces Surface Membrane (sm) CXCR4 and increases smIgM expression, particularly in unmutated IGHV (U-)CLL cells. IL-4 production by T-cells is inhibited by ibrutinib. Lymphocytosis is more frequent in treated mutated IGHV (M-)CLL, indicating increased cell death of U-CLL in tissues. How ibrutinib affects IL-4R signaling, B-cell survival, and relative sensitivity of U-CLL vs. M-CLL is so far unknown.

Pure B-cells were cultured alone or with autologous T-cells previously treated with DMSO or ibrutinib for 3 days. Ibrutinib was not administered during the 7-day incubation of T-B cells.

Both U- and M-CLL cells co-cultured with ibrutinib pre-treated T-cells had decreased expression of smIL-4R and pSTAT6. Signaling of IL-4R was inhibited due to the loss of IL-4. It was found that survival of U-CLL B-cells depended more on microenvironmental support than M-CLL B-cells.

  • Altered T-cell function in treatment naïve CLL patients administered with ibrutinib
    • Decreased numbers of IL-4-producing T-cells
    • Reduced proliferation upon stimulation with mitogen
    • Impaired homing ability to solid tissues
  • Ibrutinib impaired IL-4R and CXCR4 signaling in CLL B-cells
    • Decreased smIL-4R and inhibited IL-4 signaling
    • Increased (dysfunctional) CXCR4 signaling
    • Decreased BCL2 levels in U-CLL but not M-CLL B-cells, decreasing survival in tissue niches

In xenografts, inhibition of tumor growth and impaired CXCR4 in tissue niches was greater in U-CLL than M-CLL B-cells. Ibrutinib also significantly reduced growth of T-cells only in U-CLL xenografts.


Shih-Shih Chen concluded the presentation by stating that ibrutinib treatment results in a dual loss of environmental pro-survival signaling:

  • Ibrutinib alters the microenvironment by reducing T-cell IL-4 production
  • Ibrutinib interrupts the IL-4R – IL-4 axis by inhibiting smIL-4R expression and IL-4-mediated signaling; results in decreased survival by reducing BCL2 protein levels
  • U-CLL are more susceptible to this than M-CLL B-cells; U-CLL are more likely to die in tissue niches, explaining the limited lymphocytosis reported in U-CLL cases
  • These findings support combining BTK inhibitors and BCL2 inhibitors to treat CLL

  1. Chen S.S.IL-4R – IL-4 axis Disruption by Ibrutinib Therapy Contributes to the Greater Vulnerability of U-CLL Clones to Loss of Microenvironmental Inputs. XVII International Workshop on Chronic Lymphocytic Leukemia; 2017 May 12–15; New York, USA.