Background

B-cell lymphomas (BCLs), which include chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), Waldenstrom macroglobulinaemia (WM) and so on, are the most frequent haematologic malignancies. With the development of small-molecule targeted drugs such as Bruton’s tyrosine kinase (BTK) inhibitors (BTKis), B-cell lymphoma 2 inhibitors, and phosphoinositide 3-kinase (PI3K) inhibitors, treatment of BCL has undergone a tremendous change, especially for CLL. The use of BTKis, in particular, has benefited many patients, including those at high risk. The first-generation BTKi ibrutinib inhibits the proliferation and survival of B cells by irreversibly binding BTK C481 and blocking the B-cell receptor (BCR) signalling pathway. Ibrutinib also binds to other kinases, such as IL-2-inducible T-cell kinase (ITK), epidermal growth factor receptor (EGFR) [1], and TEC and SRC family kinases [2], to induce off-target effects. Although the antitumour activities of BTKis depend on both on-target and off-target effects, adverse events such as rashes, atrial fibrillation, and bleeding should not be ignored. The next-generation BTKis acalabrutinib, zanubrutinib, and orelabrutinib show higher selectivity and fewer off-target effects than ibrutinib, thereby limiting the adverse events profoundly. Till date, the inhibitors have been successfully approved for the treatment of relapsed/refractory (R/R) MCL and CLL. Recently, zanubrutinib has been approved for WM. Non-covalent BTKis, such as pirtobrutinib, vecabrutinib, and fenebrutinib, may have fewer adverse effects than the covalent BTK inhibitors and have shown promising safety profiles and efficacy in clinical trials.

Treatment with a BTKi potentially impacts both innate and adaptive immunity, including the number and function of various immune cells. BTK looks like a type of ‘Swiss Army knife’ and is expressed in myeloid and other innate immune cells. Thus, inhibition of BTK with a BTKi leads to changes in immune cell numbers. Additionally, different BTKis play pleiotropic roles (different effects on different types of target cells) in the regulation of immune cell function. Ibrutinib inhibits rituximab-dependent NK cell-mediated cytotoxicity, while acalabrutinib, orelabrutinib, and fenebrutinib have no effect on ITK- and NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), making them promising candidates for combination therapy with anti-CD20 antibodies. In addition, the influence of ibrutinib on T cells provides a rationale for the combined use of programmed cell death-ligand 1 (PD-L1) inhibitors, chimeric antigen receptor-T-cell (CAR-T) therapy, or bispecific antibody (BiAb) with a BTKi. Despite having no inhibitory effect on ITK, the next-generation BTKi acalabrutinib benefits CAR-T therapy; however, the exact mechanism remains unclear [3].

Tumour microenvironment (TME) plays a crucial role in the survival and growth of tumour cells by providing inhibitory or stimulatory signals, including BCR signals [4]. BTK can transmit and enhance molecular signals on the surface of various cells that communicate with the TME, via the Toll-like receptor (TLR) and FcγR on macrophages, dendritic cells, mast cells, and basophils [5]. In addition, BTK is a regulator of the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome, which has been observed to be associated with various infections, including coronavirus disease 2019 (COVID-19), myocardial infarction, and other diseases such as Alzheimer’s disease and atherosclerosis [6]. Among the side effects, infections are associated with severity and poor prognosis in patients and are particularly complicated to manage. Moreover, BTKis have recently been shown to impact vaccination [7].

At present, the mechanisms of combination strategies of BTKis with specific immunotherapies are unclear. In addition, infections caused by the use of BTKis are common in clinical practice but have not attracted sufficient attention yet. Therefore, comprehensive exploration and understanding of these issues are urgently required. This review aimed to examine the pleiotropic effects of BTKis on the immune system and the potential combination strategies comprising BTKi and different immunotherapies, which may provide practical advice on the management of BTKi-related toxicity and shed light on optimal treatment options.

BCR/BTK signaling in normal and malignant B cells

BCR is a transmembrane protein complex that controls B-cell fate from the beginning of its expression in the form of pro-BCR and pre-BCR and thus guides cell maturation, survival, apoptosis and the production of antibodies in plasma cells [8, 9]. BCR signaling is connected by a network of kinases and phosphatases that tune and amplify its activation. In general, BCR signaling pathways can be classified into two types: chronically activated BCR and tonic BCR [10]. Chronically activated BCR is an antigen-dependent process mainly utilizing the canonical nuclear factor-kB (NF-kB) pathway, MAPK/ERK pathways and ect. Conversely, tonic BCR maintains B cell survival through PI3K/AKT pathway by antigen-independent process [9, 11] (Fig. 1).

Fig. 1
figure 1

Upon antigen binding to the BCR, Src-family kinases such as LYN tyrosine kinase (LYN) and spleen tyrosine kinase (SYK) phosphorylate immunoreceptor tyrosine-based activation motif (ITAM) of Igα and Igβ, thereby recruiting spleen tyrosine kinase (SYK). SYK then phosphorylates and activates BTK. Subsequently, BTK phosphorylates phospholipase-Cg2 (PLCG2), and further initiates a series of downstream signaling pathways including nuclear factor kappa B (NF-kB), mitogen-activated protein kinase (MAPK), CaM and other pathways that promote cell proliferation and survival. In addition, BTK can also transmit various surface molecular signals such as Toll-like receptors (TLRs) that B cells communicate with the microenvironment; Tonic BCR: LYN also phosphorylates tyrosine residues in the cytoplasmic tail of the BCR co-receptor CD19, which countributes to the activation of phosphoinositol-3 kinase (PI3K) /AKT/mTOR signaling in antigen-independent manner

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BTK is a non-receptor intracellular kinase that belongs to the TEC family of tyrosine kinases, together with bone marrow-expressed kinase (BMX), redundant-resting lymphocyte kinase, and ITK. BTK has: (i) a kinase domain with enzymatic activity, (ii) SRC homology (SH) domains (including SH2 and SH3), (iii) a TEC homology (TH) domain, and (iv) an N-terminal pleckstrin homology (PH) domain [12, 13] (Fig. 2). BTK acts as a crucial component to couple BCR to more distal signaling, whose inactivation results in defects in B-cell development and function [14]. Upon BCR activation, BTK is recruited to the plasma membrane from cytoplasm by its PH domain binding phosphatidylinositol (3,4,5)-trisphosphate. At the plasma membrane, BTK is phosphorylated by SYK and SRC kinases at Y551 in the kinase domain and then autophosphorylates Y223 in its SH3 domain [14]. Phosphorylated BTK activates PLCG2 to further trigger a series of downstream signaling cascades.

Fig. 2
figure 2

The structure of BTK. BTK protein includes 659 amino acids and 5 domains (PH, TH, SH3, SH2, Kinase domain). Among them, Y223 in the SH3 domain and Y551 in the kinase domain are two critical tyrosine phosphorylation sites. The covalent BTK inhibitors, including ibrutinib, acalabrutinib, zanubrutinib, and tirabrutinib, selectively bind to C481 residue in kinase domain. The non-covalent BTK inhibitors do not bind to C481. For example, Fenebrutinib forms hydrogen bonds with K430, M477, and D539 residues

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Constitutive BCR or aberrant BTK activation usually lead to B-cell malignant transformation, which has been implicated in the pathogenesis of various BCLs. Moreover, malignant B cells often hijack normal BCR/BTK pathways to maintain their growth and survival [15]. BTKi was thus designed and developed successfully to target BCR/BTK signaling for the treatment of BCLs. However, since other kinases such as ITK, TEC, and BMX also harbour a corresponding residue in the ATP-binding site, a series of off-target effects, including bleeding, atrial fibrillation, and infection can, occur.

First-generation and next-generation BTKis

Ibrutinib is a first-generation covalent irreversible BTKi that binds to C481 within the BTK active site and acts as a potent ATP competitive inhibitor, with a half-maximal inhibitory concentration of 0.5 nM. It can covalently inhibit other kinases, including ITK, TEC, EGFR, ErbB2, ErbB4, BMX, JAK3, and HER2 [16]. The off-target inhibitions of these kinases lead to a variety of adverse events. The most common adverse event in patients with CLL is infection (83%) that may be related to the inhibition of ITK in T cells and that of BTK in neutrophils and macrophages [17]. Bleeding and atrial fibrillation are among the frequent side effects of ibrutinib, the latter inhibiting BTK and TEC kinases, resulting in impaired platelet activation and cardiac PI3K-Akt pathway downregulation [18, 19]. Diarrhoea was reported in 52% of patients with CLL, who were treated with ibrutinib, due to the inhibition of EGFR by the latter [17, 20]. To reduce these off-target effects and improve tolerability, next-generation BTKis, such as acalabrutinib, zanubrutinib, and orelabrutinib, have been designed and developed to covalently attach to BTK via C481, exhibiting greater selectivity for BTK and having fewer off-target effects than ibrutinib. Non-covalent BTK inhibitors, such as pirtobrutinib, vecabrutinib, and fenebrutinib, which do not bind C481, are reported to have fewer off-target toxicity, thus providing a promising effective option for patients with B-cell lymphoma, especially those with BTK C481 mutations. Fenebrutinib does not inhibit EGFR or ITK; thus, it may greatly alleviate diarrhoea and rash due to EGFR inhibition and preserve NK cell-mediated ADCC [21]. Adverse effects of the various BTKis with relative frequencies are shown in Table 1. Recently, they have been well studied and have shown manageable safety profiles and efficacy [22]. Furthermore, the HSP90 inhibitor SNX-5422, which is also a BTK protein degrader, has been explored for BTK inhibitor-resistant CLL [23].

Table 1 The adverse effects and relative frequencies of different BTKi in B-cell malignancies
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Effects of BTK and BTKi in innate immunity

BTK is widely expressed in innate immune cells and plays a pivotal role in innate immunity [24]. It is indispensable for the development and maturation of neutrophils [25]. Neutrophil count is decreased in patients with X-linked agammaglobulinaemia due to growth arrest [26, 27]. Additionally, with exposure to ibrutinib, multiple functions of neutrophils, such as the production of reactive oxygen and engulfment of Aspergillus, are significantly impaired, which severely affects the innate immune response [28].

BTK not only induces TLR and Fc receptor signalling pathways but also regulates NLRP3-inflammasome activity in macrophages, monocytes, and dendritic cells (DCs) [29,30,31]. Macrophages can phagocytise and kill pathogens, acting as the first line of defence against fungal infections. Several studies have shown that exposure to ibrutinib and acalabrutinib can inhibit phagocytosis and secretion of inflammatory factors in macrophages and monocytes, thereby increasing susceptibility to infection [32,33,34]. In addition, ibrutinib suppresses the secretion of CXCL13, which can attract and protect CLL cells from tumour-associated macrophages or nurse-like cells in the bone marrow of patients with CLL [35]. Importantly, myeloid-derived suppressor cells (MDSCs) with BTK expression can be inhibited by ibrutinib, thereby potentially enhancing the efficacy of cancer vaccines [36]. Zou et al. [2).

The impairment of the immune system caused by BTKis aggravates CLL defects. An increasing number of infections (particularly fungal infections) and pneumonia have been reported in patients treated with ibrutinib, especially in R/R patients. The infection rate is the highest in the initial months of ibrutinib therapy and declines with decreasing tumour burden [90]. With respect to COVID-19, BTKis appeared to dampen the cytokine storm by inhibiting the monocyte/macrophage activation induced by COVID-19 and improving the survival of patients with CLL [108, 110], which raises the prospect of BTKis being useful for other diseases related to macrophage activation; long-term research in this field would be worth exploring. BTKis have been confirmed to abrogate the immune response to novel antigens, suggesting that a patient-tailored vaccination approach should be adopted in patients with CLL, according to disease status and previous treatment, such as in the early stages of the disease or before BTKi administration. Further investigations on the effects of BTKis on the immune system and potential combination therapy should be explored to provide the best clinical practice guidance to clinicians dealing with adverse events such as infections.