Potent antitumor effects of combination therapy with IFNs and monocytes in mouse models of established human ovarian and melanoma tumors

Abstract

Interferon-activated monocytes are known to exert cytocidal activity against tumor cells in vitro. Here, we have examined whether a combination of IFN-α2a and IFN-γ and human monocytes mediate significant antitumor effects against human ovarian and melanoma tumor xenografts in mouse models. OVCAR-3 tumors were treated i.t. with monocytes alone, IFN-α2a and IFN-γ alone or combination of all three on day 0, 15 or 30 post-tumor implantation. Mice receiving combination therapy beginning day 15 showed significantly reduced tumor growth and prolonged survival including complete regression in 40% mice., Tumor volumes measured on day 80 in mice receiving combination therapy (206 mm3) were significantly smaller than those of mice receiving the IFNs alone (1041 mm3), monocytes alone (1111 mm3) or untreated controls (1728 mm3). Similarly, combination therapy with monocytes and IFNs of much larger tumor also inhibited OVCAR-3 tumor growth. Immunohistochemistry studies showed a large number of activated macrophages (CD31+/CD68+) infiltrating into OVCAR-3 tumors and higher densities of IL-12, IP10 and NOS2, markers of M1 (classical) macrophages in tumors treated with combination therapy compared to the controls. Interestingly, IFNs activated macrophages induced apoptosis of OVCAR-3 tumor cells as monocytes alone or IFNs alone did not mediate significant apoptosis. Similar antitumor activity was observed in the LOX melanoma mouse model, but not as profound as seen with the OVCAR-3 tumors. Administration of either mixture of monocytes and IFN-α2a or monocytes and IFN-γ did not inhibit Lox melanoma growth; however a significant inhibition was observed when tumors were treated with a mixture of monocytes, IFN-α2a and IFN-γ. These results indicate that monocytes and both IFN-α2a and IFN-γ may be required to mediate profound antitumor effect against human ovarian and melanoma tumors in mouse models.

Decreased NK cell functions in obesity can be reactivated by fat mass reduction

“…monocytes, macrophages, T cells and NK cells (33). An animal study showed increased regression of tumor nodules and survival of animals after treatment with IFN-c (34).…”

Effects of tyrosine kinase inhibitors alone or in combination with vaccine on tumor-infiltrating myeloid cells

“…We evaluated granulocytes (Gr1 + CD11b - ), MDSCs (Gr1 + CD11b + ), and tumor-associated macrophages (TAMs, Gr1 - CD11b + ). Markers utilized to identify activation were FasL [1], CXCL9 [2], CD31 [3], and CD105 [4]. …”

Monocyte and interferon based therapy for the treatment of ovarian cancer

“…We have expanded this observation to show that IFNs are potent killers of ovarian cancer cells lines, and there is synergism with the IFNs and the current standard of care of carboplatin and paclitaxel[54]. IFN-α can also induce tumor cell apoptosis by stimulating the tumor cells to produce the cell death ligand TRAIL, which through an autocrine feedback loop, kills the tumor cells expressing the receptors for TRAIL (DR4/DR5)[55]. TRAIL signaling results in a Caspase 8 mediated cleavage of BID to tBID, followed by Bak dimerization, loss of mitochondrial membrane potential and release of apoptosis inducing factor which results in cell death in ovarian cancer cells (OVCAR3)[55].…”

“…In 2007 we showed that while IFNs were capable of inducing cytotoxicity in a number of cancer cell lines, the addition of monocytes to the culture significantly increased the cytotoxicity[53]. Using a intratumoral injection, mouse model with an human ovarian cancer cell line we showed that while there was no significant reduction in tumor size with IFNs or monocytes alone, there was significant decrease in tumor volume and complete response in some animals that received injection of IFNs and monocytes at the time of tumor initiating[55]. Importantly administration of IFNs and monocytes 15 days after the injection of tumor cells exhibited a similar response to Day 0 in both tumor volume and complete response.…”