Dasatinib, a Src kinase inhibitor and a preclinical drug for chronic-phase chronic myeloid leukaemia, is also on the study list. As reported, learn more dasatinib could reduce MMP9+ macrophage density and inhibit MMP9 expression in the tumour microenvironment. This observation broadened the therapeutic mechanisms of dasatinib. To deplete TAMs by targeting their surface molecules with immunotoxin-conjugated agents is another approach for tumour therapy. Such studies have been conducted for ovarian cancer treatment by using immunotoxin-conjugated mAbs, where the surface proteins of TAMs, such as scavenger
receptor-A and CD52, were targeted.[62, 63] Folate receptor β (FRβ) is another surface protein worth targeting because it is over-expressed in M2-like TAMs,[64, 65] and the existence of FRβ+ macrophages positively associates with high vessel density, high incidence of haematogenous metastasis and a poor prognosis in patients with pancreatic cancer. Nagai et al. reported the inhibitory effects of the folate–immunotoxin conjugate on tumour growth, accomplished with the depletion of TAMs. One benefit of this approach may be that while pro-tumoral M2 TAMs could be depleted, the M1 tumoricidal ones are not affected. Recent studies demonstrate that several bacteria prefer to take macrophages as targets. For instance, it was reported Selleckchem Sirolimus that
Shigella flexneri infection could selectively induce the apoptosis of macrophages, and a single injection of an attenuated strain of Shigella flexneri to tumour-bearing mice resulted in the apoptosis of TAMs, followed by a 74% reduction in size of tumours. In addition, other bacteria, such as Salmonella typhimurium, Listeria monocytogens, Chlamydia psittaci and Legionella pneumophila, are
also considered to be useful for TAM-targeted immunotherapy because they harbour primarily in macrophages. Other than directly inducing the apoptosis of TAMs as mentioned above, another available approach for TAM suppression is to evoke acquired immune responses, in which cytotoxic T lymphocytes act as the scavengers of TAMs because they can naturally target the membrane molecules of macrophages. Thalidomide In other words, up-regulating the membrane molecules that could be recognized by T cells in TAMs would be a potential method of TAM depletion. One such molecule is legumain, a lysosomal protease highly expressed in many human tumours; which promotes neoplastic cell invasion and metastasis. Luo et al. originally found that legumain is over-expressed in M2-like TAMs. In the following studies, they immunized tumour-bearing mice with a novel legumain-based DNA vaccine, and found that this vaccine activated dendritic cells, which then triggered multi-step reactions including the antigen presenting, co-stimulation of cytotoxic CD8+ T cells and the specific abrogation of legumain-expressing TAMs.