Vascular-targeted TNFα and IFNγ inhibits orthotopic colorectal tumor growth

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.

Anti‐cancer therapy with TNFα and IFNγ: A comprehensive review

“…Absence of either TNFR1 signalling or IFNγ signalling determined Tag‐specific Th1 cells to induce tumour dormancy or promote multistage carcinogenesis, which was another solid evidence supporting the co‐operative effects of TNFα and IFNγ in anti‐tumour treatment. Our recent study using tumour vasculature homing peptide TCP‐1 showed that targeted combination therapy with TCP‐1/TNFα and TCP‐1/IFNγ could remarkably inhibit orthotopic colorectal tumour growth by inducing tumour necrosis without causing significant systematic toxicity . The anti‐tumour effects of TNFα and IFNγ either using alone or in combination are summarized in Figure .…”

“…Our recent study using tumour vasculature homing peptide TCP-1 showed that targeted combination therapy with TCP-1/TNFα and TCP-1/IFNγ could remarkably inhibit orthotopic colorectal tumour growth by inducing tumour necrosis without causing significant systematic toxicity. 100 The anti-tumour effects of TNFα and IFNγ either using alone or in combination are summarized in Figure 1. Our result emphasizes the therapeutic potential of co-administration of targeted TNFα and IFNγ for cancer treatment and the utility of TCP-1 peptide as a tumour-targeting agent in colorectal cancer.…”

Strategy to targeting the immune resistance and novel therapy in colorectal cancer

“…In mouse models of highly aggressive mesenchymal CRC tumors, a potential synergistic effect was observed with the combination of a TGFR inhibitor with a PD‐1 checkpoint inhibitor , or with an agonistic OX40 mAb , which enhanced effector function and survival of activated T cells. The positive treatment outcome was associated with an expansion of tumor‐infiltrating effector CTLs and TH1 cells, enhanced antitumor T‐cell immunity , and a high tumor‐specific IFN‐ γ response . Alternative immunotherapeutic approaches to be explored in inflamed TGF‐ β ‐mediated mesenchymal tumors include pharmacological elimination of MDSCs or blockade of related immunosuppressive chemokine signaling circuits and pathways, as demonstrated in other malignancies with an immune‐evasive microenvironment .…”

Nonviral Gene Therapy for Cancer: A Review

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