Jin Qiu1, Shiwen Peng2, Andrew Yang2, Ying Ma3, Liping Han4, Max A Cheng5, Emily Farmer5, Chien-Fu Hung6, T-C Wu7. 1. Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States. 2. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States. 3. Department of Gynecology and Obstetrics, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong province, China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States. 4. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States. 5. Department of Pathology; Johns Hopkins Medical Institutions, Baltimore, MD, United States. 6. Department of Pathology and Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States. 7. Departments of Pathology, Department of Obstetrics and Gynecology, Department of Molecular Microbiology and Immunology, and Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
Abstract
Purpose: Mucosal immunization is suggested to be crucial for controlling tumors in the mucosal region; however, therapeutic DNA vaccination with electroporation in various mucosal sites has yet to become clinically adaptable. Since tumor-draining lymph nodes (tdLNs) have been suggested as immune-educated sites that can be utilized to mount a potent antitumor immune response, we examined whether intramuscular DNA vaccination with electroporation at sites that target the mucosal tdLNs could elicit mucosal immune response to restrict tumor growth. Experimental Design: The efficacy and mechanism of intramuscular administration of a therapeutic DNA vaccine with electroporation at different sites was examined by lymphocyte analysis, tumor growth, mouse survival, as well as integrin expression, in mice bearing orthotopic HPV16 E6/E7+ syngeneic TC-1 tumors in various mucosal areas. Results: While provoking comparable systemic CD8+ T cell responses, intramuscular hind leg vaccination generated stronger responses in cervicovaginal-draining LNs to control cervicovaginal tumors, whereas intramuscular front leg vaccination generated stronger responses in oral-draining LNs to control buccal tumors. Surgical removal of tdLNs abolished the antitumor effects of therapeutic vaccination. Mucosal-tdLN-targeted intramuscular vaccination induced the expression of mucosal-homing integrins LPAM-1 and CD49a by tumor-specific CD8+ T cells in the tdLNs. Inhibition of these integrins abolished the therapeutic effects of vaccination and the infiltration of tumor-specific CD8+ T cells into mucosal tumors. Conclusions: Our findings demonstrate that tumor draining lymph nodes targeted intramuscular immunization can effectively control mucosal tumors, which represents a readily adaptable strategy for treating mucosal cancers in humans.
Purpose: Mucosal immunization is suggested to be crucial for controlling tumors in the mucosal region; however, therapeutic DNA vaccination with electroporation in various mucosal sites has yet to become clinically adaptable. Since tumor-draining lymph nodes (tdLNs) have been suggested as immune-educated sites that can be utilized to mount a potent antitumor immune response, we examined whether intramuscular DNA vaccination with electroporation at sites that target the mucosal tdLNs could elicit mucosal immune response to restrict tumor growth. Experimental Design: The efficacy and mechanism of intramuscular administration of a therapeutic DNA vaccine with electroporation at different sites was examined by lymphocyte analysis, tumor growth, mouse survival, as well as integrin expression, in mice bearing orthotopic HPV16 E6/E7+ syngeneic TC-1 tumors in various mucosal areas. Results: While provoking comparable systemic CD8+ T cell responses, intramuscular hind leg vaccination generated stronger responses in cervicovaginal-draining LNs to control cervicovaginal tumors, whereas intramuscular front leg vaccination generated stronger responses in oral-draining LNs to control buccal tumors. Surgical removal of tdLNs abolished the antitumor effects of therapeutic vaccination. Mucosal-tdLN-targeted intramuscular vaccination induced the expression of mucosal-homing integrins LPAM-1 and CD49a by tumor-specific CD8+ T cells in the tdLNs. Inhibition of these integrins abolished the therapeutic effects of vaccination and the infiltration of tumor-specific CD8+ T cells into mucosal tumors. Conclusions: Our findings demonstrate that tumor draining lymph nodes targeted intramuscular immunization can effectively control mucosal tumors, which represents a readily adaptable strategy for treating mucosal cancers in humans.
Authors: Cornelia L Trimble; Shiwen Peng; Christopher Thoburn; Ferdynand Kos; T C Wu Journal: Cancer Immunol Immunother Date: 2009-12-13 Impact factor: 6.968
Authors: Ronald D Alvarez; Warner K Huh; Sejong Bae; Lawrence S Lamb; Michael G Conner; Jean Boyer; Chenguang Wang; Chien-Fu Hung; Elizabeth Sauter; Mihaela Paradis; Emily A Adams; Shirley Hester; Bradford E Jackson; T C Wu; Cornelia L Trimble Journal: Gynecol Oncol Date: 2015-11-23 Impact factor: 5.482