Secondary lymphoid organs, which are also called proliferation centers, have a more complex microenvironment that is more conducive to CLL cell survival ( 18), and this is where the BCR signaling activity of CLL cells is upregulated, and the proliferative activity of CLL cells is also increased ( 18, 26). Overall regulation of ibrutinib on CLL microenvironment Therefore, this article reviews the effects of ibrutinib on the microenvironment and cellular immunity of patients with CLL, particularly on the behavior and function of T cells, and their potential mechanisms, to provide a basis for the clinical benefits of long-term ibrutinib treatment and the further design of combined therapy based on T-cell-based immunotherapies. However, to date, the effect of ibrutinib on the microenvironment and T-cell immunity of patients with CLL is not completely clear. This activity has been confirmed by significant improvement in the efficacy of CAR-T cells and the bispecific antibody blinatumomab in the clinic ( 3, 23– 25). Nevertheless, previous studies have shown that ibrutinib not only inhibits BCR and nuclear factor kappa B (NF-κB) signaling ( 17– 19) but also plays multiple roles in regulating the tumor microenvironment and T-cell immunity in CLL patients ( 20– 22). Both acalabrutinib and zanubrutinib have demonstrated higher selectivity and fewer off-target effects than ibrutinib ( 11, 15, 16). Ibrutinib, as the first BTKi, has profoundly altered the treatment paradigm of CLL patients, particularly relapsed/refractory CLL (R/R CLL) and high-risk patients with TP53 aberrations ( 12– 14). Second-generation BTKis, such as fenibrutinib, vecabrutinib, and nembrolizumab, can reversibly inhibit BTK and to some extent overcome the drug resistance of first-generation BTKis ( 11). First-generation BTK inhibitors (BTKis), such as ibrutinib, acalabrutinib, and zanubrutinib, are irreversible at the C418 site of BTK ( 11). BCR signaling is initiated through upstream kinases, including SYK, BTK, and PI3K, and these can be inhibited by corresponding small-molecule kinase inhibitors ( 10). The B-cell receptor (BCR) signaling pathway in CLL cells is reportedly overactivated thus, targeting the key kinases of the BCR pathway is a promising anti-leukemia therapy. Therefore, reversing microenvironment disorders and reconstituting T-cell immunity may be critical to improving the outcome of CLL patients ( 8, 9). Moreover, CD8 + T cells demonstrate an “exhausted” phenotype with progressive loss of effector function and impaired memory T-cell potential ( 6, 7). T cells in CLL patients, as major supporting cells in the tumor microenvironment and particularly CD4 + T cells, nourish CLL cells through complex cytokine networks or direct contact ( 5). Tumor microenvironment disorder and T-cell immune dysfunction are prominent characteristics of CLL that are clinically manifested as increased susceptibility to opportunistic infections such as viruses and fungi and an increased incidence of autoimmune diseases and secondary malignant tumors ( 2), which are also the main causes of failure of T-cell-based immunotherapies and drug resistance ( 3, 4). In this review, we summarize the current evidence for the effects of ibrutinib on the tumor microenvironment and cellular immunity of patients with CLL, particularly for the behavior and function of T cells, explore its potential mechanisms, and provide a basis for the clinical benefits of long-term ibrutinib treatment and combined therapy based on T-cell-based immunotherapies.Ĭhronic lymphocytic leukemia (CLL) is a malignancy of small, mature B lymphocytes that clonally expand into secondary lymphoid organs, bone marrow, and peripheral blood, resulting in lymphadenopathy, splenomegaly, and hematopoietic failure ( 1, 2). For example, ibrutinib not only reverses the tumor microenvironment by blocking cytokine networks and toll-like receptor signaling but also regulates T cells in number, subset distribution, T-cell receptor (TCR) repertoire and immune function by inhibiting interleukin-2 inducible T-cell kinase (ITK) and reducing the expression of inhibitory receptors, and so on. In addition to targeting B-cell receptor (BCR) signaling to kill tumor cells, increasing evidence has suggested that ibrutinib regulates the tumor microenvironment and T-cell immunity in a direct and indirect manner. Ibrutinib is the first irreversible inhibitor of Bruton’s tyrosine kinase (BTK). Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, ChinaĬhronic lymphocytic leukemia (CLL), a highly heterogeneous B-cell malignancy, is characterized by tumor microenvironment disorder and T-cell immune dysfunction, which play a major role in the proliferation and survival of CLL cells.Yanyan Liu, Yongping Song * and Qingsong Yin *
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