Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

Abstract

B-cell receptor (BCR) signaling and tumor–microenvironment crosstalk both drive chronic lymphocytic leukemia (CLL) pathogenesis. Within the microenvironment, tumor cells shape the T-cell compartment, which in turn supports tumor growth and survival. Targeting BCR signaling using Bruton tyrosine kinase inhibitors (BTKi) has become a highly successful treatment modality for CLL. Ibrutinib, the first-in-class BTKi, also inhibits Tec family kinases such as interleukin-2–inducible kinase (ITK), a proximal member of the T-cell receptor signaling cascade. It is increasingly recognized that ibrutinib modulates the T-cell compartment of patients with CLL. Understanding these T-cell changes is important for immunotherapy-based approaches aiming to increase the depth of response and to prevent or treat the emergence of resistant disease. Ibrutinib has been shown to improve T-cell function in CLL, resulting in the expansion of memory T cells, Th1 polarization, reduced expression of inhibitory receptors and improved immune synapse formation between T cells and CLL cells. Investigating the modulation of BTKi on the T-cell antitumoral function, and having a more complete understanding of changes in T cell behavior and function during treatment with BTKi therapy will inform the design of immunotherapy-based combination approaches and increase the efficacy of CLL therapy.

Kinase inhibitors developed for treatment of hematologic malignancies: implications for immune modulation in COVID-19

“… 79 In addition, ibrutinib polarizes the T-cell population toward effector cells and reduces their exhaustion marker expression, which possibly enables the adaptive immune system to a more capable immune response. 56 , 80 B-cell activation and a subsequent increase in IgG levels, which are both inhibited by ibrutinib, are specifically increased in patients with severe COVID-19. 45 , 68 , 76 Because of these immunomodulatory effects, ibrutinib, and perhaps the more selective BTK inhibitors as well, might be beneficial in the early and late stages of COVID-19.…”

“… 54 Ibrutinib, as well as the more selective BTK inhibitors, reduces the (over)activated T-cell state of CLL patients, as measured by lower plasma cytokine levels and decreased exhaustion. 47 , 55 , 56 These observations are probably the indirect result of on-target (BTK) effects on leukemia cells, resulting in decreased suppressive interactions of the malignant B cells with T cells. 57 Sorafenib and sunitinib treatment also results in lower PD-1 expression on CD4 + and CD8 + T cells in vivo and in vitro, respectively.…”

Follicular Lymphoma Microenvironment: An Intricate Network Ready for Therapeutic Intervention

“…In chronic lymphocytic leukemia (CLL), it has been demonstrated that ibrutinib profoundly reshapes the T cell compartment, improving T cell function. Ibrutinib induces expansion of memory T cells, Th1 polarization, reduces the expression of inhibitory receptors (i.e., PD-1 and CTL-4), and improves immune synapse between T cells and CLL cells [ 103 , 104 ]. However, no data are available for FL in this regard.…”

TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia

“…Indeed, and at variance from chemoimmunotherapy, ibrutinib mitigates the immune dysregulation induced by CLL, by modifying the absolute number of T-cells (25)(26)(27)(28), the T-cell receptor repertoire (26,29), the T-cell maturation (27,28), the Th1 and Th2 polarization (24)(25)(26)(27), the Th17 and Treg cell balance (25,27,28), the T cell inhibitory receptors and function (25,(27)(28)(29). These effects, all modulated toward an anti-tumor T-cell response, have been nicely reviewed (30)(31)(32). Regarding the Th1 and Th2 polarization, it has been shown that ibrutinib may contribute to revert the Th2-dominant response observed in CLL, thus influencing T-cell mediated cancer immune surveillance, in vitro and in a mouse model (24) and in patients treated with ibrutinib (25)(26)(27).…”