Intramuscular vaccination targeting mucosal tumor draining lymph node enhances integrins-mediated CD8+ T cell infiltration to control mucosal tumor growth

Jin Qiu, Shiwen Peng, Andrew Yang, Ying Ma, Liping Han, Max A. Cheng, Emily Farmer, Chien-Fu Hung, Tzyy Choou Wu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalOncoImmunology
DOIs
StateAccepted/In press - May 23 2018

Fingerprint

Integrins
Vaccination
Lymph Nodes
T-Lymphocytes
Growth
Neoplasms
Electroporation
Therapeutic Uses
Immunization
Leg
Mucosal Immunity
DNA Vaccines
Cheek
DNA
Research Design

Keywords

  • CD49a
  • Immunotherapy
  • LPAM-1
  • Mucosal immunity
  • Tumor draining lymph node

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Intramuscular vaccination targeting mucosal tumor draining lymph node enhances integrins-mediated CD8+ T cell infiltration to control mucosal tumor growth. / Qiu, Jin; Peng, Shiwen; Yang, Andrew; Ma, Ying; Han, Liping; Cheng, Max A.; Farmer, Emily; Hung, Chien-Fu; Wu, Tzyy Choou.

In: OncoImmunology, 23.05.2018.

Research output: Contribution to journalArticle

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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.",
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AU - Qiu, Jin

AU - Peng, Shiwen

AU - Yang, Andrew

AU - Ma, Ying

AU - Han, Liping

AU - Cheng, Max A.

AU - Farmer, Emily

AU - Hung, Chien-Fu

AU - Wu, Tzyy Choou

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