title: Cancer immunotherapy employing an innovative strategy to enhance CD4+ T cell help in the tumor microenvironment.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University Shanghai, China; Pharmacy School of Fudan University, Shanghai, China; Department of Pharmacology and Toxicology, Shanghai Institute of Planned Parenthood Research, Shanghai, China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America.
authors.forename: Liwen
authors.initials: L
authors.lastname: Song
authors.affiliation: General Surgery and Surgical Intensive Care, Kaohsiung Veterans General Hospital, Taiwan.
authors.forename: Ming-Chieh
authors.initials: MC
authors.lastname: Yang
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America.
authors.forename: Jayne
authors.initials: J
authors.lastname: Knoff
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America; Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America; Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States of America.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage*; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D007111:Immunity, Cellular / Q000276:immunology; D007167:Immunotherapy; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D017780:Malaria Vaccines / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage*; D050725:Papillomavirus E7 Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; D017780:Malaria Vaccines; D009838:Oligodeoxyribonucleotides; C401223:PADRE 45; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16; D002945:Cisplatin