TABLE 4.

Effects of ibrutinib and acalabrutinib on MDSCs, DCs and osteoclasts.

Cells	Inhibitor	Target	Signaling pathway	Effects	References
MDSCs	Acalabrutinib	BTK	Unclear	Reduces peripheral blood granulocytic MDSCs in patients with advanced pancreatic cancer and metastatic urothelial carcinoma	Overman et al., 2020; Zhang et al., 2020
	Ibrutinib	BTK	Unclear	Decreases the elevated counts of MDSCs in CLL patients	Solman et al., 2020, 2021
				Reduces MDSCs in the spleen and tumor in mice bearing transplanted solid tumors	Stiff et al., 2016; Varikuti et al., 2020
					Ishfaq et al., 2021
				Induces the maturation of MDSCs toward CD11c+MHCII+ DCs in vitro and in mice bearing transplanted E0771 mammary tumors	Varikuti et al., 2020
				Inhibits MDSC-mediated suppression of T-cell proliferation and activation	Stiff et al., 2016; Ishfaq et al., 2021
				Reduces the expression of adhesion molecules CD49D and CD11a on MDSCs	Stiff et al., 2016
			GM-CSFR/IL-6R-BTK	Inhibits GM-CSF+IL-6-induced in vitro generation of MDSCs from normal human blood monocytes	Stiff et al., 2016
				Reduces GM-CSF+IL-6-induced Ido1 expression in in vitro generated MDSCs	Stiff et al., 2016
			TLR4-MyD88-BTK	Inhibits LPS-induced expression of Arg1, Nos2, Ido1 and Tgfb as well as production of TNFα and NO in MDSCs	Stiff et al., 2016
			GM-CSFR-BTK	Impairs GM-CSF-induced migration of MDSCs	Stiff et al., 2016
			CXCR4-BTK	Inhibits CXCL12-induced in vitro migration and in vivo migration of MDSCs into the TME	Stiff et al., 2016; Conniot et al., 2019
DCs	Ibrutinib		Unclear	Gradually increases the counts of plasmacytoid DCs in CLL patients	Solman et al., 2021
		BTK	GM-CSFR-BTK	Accelerates GM-CSF-induced maturation, down-regulates the expression of Ly6C and up-regulates MHC class II and CD80 in DCs	Natarajan et al., 2016a
			TLR4-MyD88-BTK	Decreases LPS-induced up-regulation of CD86 and production of IL-6, IL-12 and NO in differentiating BMDCs	Natarajan et al., 2016a
				Increases LPS-induced upregulation of MHC class II, CD80 and CCR7, production of IFNβ and IL-10, and the ability to activate CD4 T cells in differentiating BMDCs	Natarajan et al., 2016a
				Inhibits LPS-induced production of TNFα and NO as well as expression of MHC class II and CD86 in differentiated BMDCs	Natarajan et al., 2016a
				Elevates LPS-induced up-regulation of CD80, production of IL-6, IL-18, IL-10 and TGFβ,and the ability to drive Th17 response in differentiated BMDCs	Natarajan et al., 2016a
			TLR7-MYD88-BTK	Attenuates imiquimod-induced oxidative stress and production of IL-23 and TNFα in dermal and splenic DCs	Al-Harbi et al., 2020; Nadeem et al., 2020
			TLR9-MYD88-BTK-STAT3/STAT1	Impairs CpG-induced up-regulation of CD86, CD83, CD80 and HLA-DR as well as production of IL-6, IL-12, TNFα and IL-10	Lougaris et al., 2014
Osteoclasts	Acalabrutinib	BTK	RANK-BTK-PLCγ1/γ2-NFATc1/c-Fos/NF-κB	Inhibits RANKL-induced osteoclast differentiation from monocytes or macrophages	Pokhrel et al., 2019; Liu et al., 2021
				Reduces the bone-resorbing activities of osteoclasts induced by RANKL and M-CSF	Pokhrel et al., 2019
				Ameliorates bone damage and arthritis severity in a mouse model of collagen-induced arthritis	Liu et al., 2021
			TLR4-MyD88-BTK-NFATc1/c-Fos	Inhibits LPS-induced osteoclast differentiation from RANKL-primed osteoclast precursors	Pokhrel et al., 2019
				Protects against Porphyromonas gingivalis LPS- induced alveolar bone erosion in a mouse model of periodontitis	Pokhrel et al., 2019
	Ibrutinib	BTK	RANK-BTK-PLCγ1/γ2-NFATc1/SRC	Inhibits RANKL-induced osteoclast differentiation from monocytes or macrophages	Shinohara et al., 2014; Liu et al., 2021
				Reduces the bone-resorbing activities of osteoclasts induced by RANKL and M-CSF	Shinohara et al., 2014
				Protects against bone loss in a mouse model of RANKL-induced osteoporosis	Shinohara et al., 2014
				Ameliorates bone damage and arthritis severity in a mouse model of collagen-induced arthritis	Liu et al., 2021