Abstract
Chemotherapy and/or radiation therapy are widely used as cancer treatments, but the antitumor effects they produce can be enhanced when combined with immunotherapies. Chemotherapy kills tumor cells, but it also releases tumor antigen and allows the cross-presentation of the tumor antigen to trigger antigen-specific cell-mediated immune responses. Promoting CD4+ T helper cell immune responses can be used to enhance the cross-presentation of the tumor antigen following chemotherapy. The pan HLA-DR binding epitope (PADRE peptide) is capable of generating antigen-specific CD4+ T cells that bind various MHC class II molecules with high affinity and has been widely used in conjunction with vaccines to improve their potency by enhancing CD4+ T cell responses. Here, we investigated whether intratumoral injection of PADRE and the adjuvant CpG into HPV16 E7-expressing TC-1 tumors following cisplatin chemotherapy could lead to potent antitumor effects and antigen-specific cell-mediated immune responses. We observed that treatment with all three agents produced the most potent antitumor effects compared to pairwise combinations. Moreover, treatment with cisplatin, CpG and PADRE was able to control tumors at a distant site, indicating that our approach is able to induce cross-presentation of the tumor antigen. Treatment with cisplatin, CpG and PADRE also enhanced the generation of PADRE-specific CD4+ T cells and E7-specific CD8+ T cells and decreased the number of MDSCs in tumor loci. The treatment regimen presented here represents a universal approach to cancer control.
Highlights
Chemotherapy and/or radiation therapy are widely used as cancer treatments
Mice in group 1 were untreated, those in group 2 were treated with cisplatin followed by intratumoral CpG, those in group 3 were treated with cisplatin followed by intratumoral PADRE peptide, those in group 4 were treated with intratumoral CpG and PADRE, and those in group 5 were treated with cisplatin followed by intratumoral CpG and PADRE (Fig. 1A)
We have shown that treatment with cisplatin followed by intratumoral injection of a potent adjuvant, CpG, and a Pan HLA-DR reactive epitope, PADRE peptide, generates potent antigen-specific cell-mediated immune responses and antitumor effects
Summary
Chemotherapy and/or radiation therapy are widely used as cancer treatments. Both chemotherapy and radiation therapy have been shown to transform the tumor microenvironment into a suitable setting for subsequent immunotherapeutic vaccination [1, 2]. We have previously used cisplatin chemotherapy to prime the tumor microenvironment for vaccination with a recombinant protein, and found that this treatment regimen induced potent antitumor effects and antigen-specific cell-mediated immune responses [1]. Does cisplatin kill tumor cells and it releases tumor antigen and allows the cross-presentation of the tumor antigen to trigger antigen-specific cell-mediated immune responses. A strategy to enhance the cross-presentation of the tumor antigen following chemotherapy is to promote CD4+ T helper cell immune responses. The PADRE peptide has been widely used in conjunction with vaccines to improve their potency by enhancing CD4+ T cell responses [4,5,6,7]. Intratumoral administration of PADRE potentially can create PADREspecific CD4+ T helper cells to further improve cross-presentation to generate tumor antigen-specific CD8+ T cells. The employment of an immunostimulatory adjuvant with PADRE peptide may further enhance tumor antigen-specific CD8+ T cells
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