Abstract
Immune-based anti-tumor or anti-angiogenic therapies hold considerable promise for the treatment of cancer. The first approach seeks to activate tumor antigen-specific T lymphocytes while, the second, delays tumor growth by interfering with blood supply. Tumor Associated Antigens are often employed to target tumors with therapeutic drugs, but some are also essential for tumor viability. Survivin (Surv) is a member of the inhibitor of apoptosis protein family that is considered a Tumor Associated Antigen important for cancer cell viability and proliferation. On the other hand, Trypanosoma cruzi (the agent of Chagas’ disease) calreticulin (TcCRT) displays remarkable anti-angiogenic properties. Because these molecules are associated with different tumor targets, we reasoned that immunization with a Surv-encoding plasmid (pSurv) and concomitant TcCRT administration should generate a stronger anti-tumor response than application of either treatment separately. To evaluate this possibility, C57BL/6 mice were immunized with pSurv and challenged with an isogenic melanoma cell line that had been pre-incubated with recombinant TcCRT (rTcCRT). Following tumor cell inoculation, mice were injected with additional doses of rTcCRT. For the combined regimen we observed in mice that: i). Tumor growth was impaired, ii). Humoral anti-rTcCRT immunity was induced and, iii). In vitro rTcCRT bound to melanocytes, thereby promoting the incorporation of human C1q and subsequent macrophage phagocytosis of tumor cells. These observations are interpreted to reflect the consequence of the following sequence of events: rTcCRT anti-angiogenic activity leads to stress in tumor cells. Murine CRT is then translocated to the external membrane where, together with rTcCRT, complement C1 is captured, thus promoting tumor phagocytosis. Presentation of the Tumor Associated Antigen Surv induces the adaptive anti-tumor immunity and, independently, mediates anti-endothelial cell immunity leading to an important delay in tumor growth.
Highlights
About 7.6 million people die every year from cancer, accounting for 13% of the total disease-caused mortality worldwide
We have described that Trypanosoma cruzi Calreticulin (TcCRT), similar to its counterpart from vertebrates, translocates from the endoplasmic reticulum (ER) to the parasite surface
Since rTcCRT did not affect tumor cell proliferation, we performed the assay using genetic immunization with Surv together with rTcCRT s.c. inoculation (As mentioned in the Methods section, these treatments are referred below as pSurv-rTcCRT or pSurv-rHuCRT, when recombinant human CRT (HuCRT) is used instead of the parasite molecule) (Figure 1). rHuCRT was included because anti-angiogenic effects are reduced compared to rTcCRT [31]
Summary
About 7.6 million people die every year from cancer, accounting for 13% of the total disease-caused mortality worldwide. In cancerous cells a variety of genomic changes occur to facilitate self-sufficiency in growth signals, reduce sensitivity to anti-growth signals, and mediate unlimited growth, abnormal tissue invasiveness and metastasis. These changes help evade apoptosis and produce pro-angiogenic molecules, two important cancer-related processes where Survivin (Surv) and Calreticulin (CRT) participate among many other proteins [2]. When human Surv cDNA (from a colon adenocarcinoma, HT-29), cloned into a pcDNA3.1 vector (pcDNA3.1-Surv or pSurv) was injected into Balb/c mice (together with a pGM-CSF plasmid), expression of Surv protein and derived MHC-I associated peptides was observed This was followed by an interesting anti-Surv cellular immune response [11]
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