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

The second session at this year’s iwCLL was 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 Chen from 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