Abstract
BackgroundTumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally identified to show potent anti-tumor activity and immunomodulatory capability. Unfortunately, several clinical studies of relevant cancer therapy did not observe significant response in maximum tolerated dose whether given alone or in combination. We have identified a tumor vasculature homing peptide (TCP-1 peptide) which targets only the vasculature of colorectal tumors but not normal blood vessels in animals and humans. In the current study, the antitumor effect of TCP-1/TNFα and TCP-1/IFNγ alone or in combination was studied in orthotopic colorectal tumor model.MethodsTCP-1/TNFα and TCP-1/IFNγ recombinant proteins were prepared and i.v. injected to study the in vivo anticancer effect in orthotopic colorectal tumor model. Tumor apoptosis was determined by TUNEL staining and cleaved caspase-3 immunofluorescent staining. Tumor infiltrating lymphocytes were analyzed by immunofluorescent staining and flow cytometry. Western-blot was performed to examine the expression of proteins. Cell apoptosis was measured by Annexin V/PI flow cytometry.ResultsTargeted delivery of TNFα or IFNγ by TCP-1 peptide exhibited better antitumor activity than unconjugated format by inducing more tumor apoptosis and also enhancing antitumor immunity shown by increased infiltration of T lymphocytes inside the tumor. More importantly, combination therapy of TCP-1/TNFα and TCP-1/IFNγ synergistically suppressed tumor growth and alleviated systematic toxicity associated with untargeted therapy. This combination therapy induced massive apoptosis/secondary necrosis in the tumor.ConclusionsTaken together, our data demonstrate TCP-1 is an efficient drug carrier for targeted therapy of colorectal cancer (CRC). TCP-1/TNFα combined with TCP-1/IFNγ is a promising combination therapy for CRC.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-0944-3) contains supplementary material, which is available to authorized users.
Highlights
Tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally identified to show potent anti-tumor activity and immunomodulatory capability
TCP-1/tumor necrosis factor alpha (TNFα) combined with TCP-1/IFNγ induced massive cell death in the tumor (>90 %) as shown by the TUNEL staining (Fig. 3f ) and cell death of the tumor vasculature (Fig. 3g)
(See figure on previous page.) Fig. 5 TCP-1/TNFα combined with TCP-1/IFNγ induced late apoptosis/secondary necrosis. a Hochest and PI double staining of tumor frozen sections from control and TCP-1/TNFα and TCP-1/IFNγ combined treatment groups
Summary
Tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ) were originally identified to show potent anti-tumor activity and immunomodulatory capability. We have previously established an orthotopic colorectal tumor model and identified a cyclic peptide known as TCP-1. This peptide can target the vasculature of orthotopic colorectal tumors [17]. Targeted delivery of TNFα by TCP-1 peptide displayed more potent antitumor activity than unconjugated TNFα by inducing more apoptosis and destructing neovasculature in orthotopic colorectal tumors at 24 h with the dose 5 μg/mouse. TCP-1/TNFα attenuated the immunosuppressing effects of TNFα in bone marrow and spleen with marked reduction in systemic toxicity [18] These findings provide a solid proof that TCP-1/TNFα could be used to treat CRC through synergistic effects with standard chemotherapeutic agents as targeted therapy
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