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Published on: October 30, 2013
CD4+ T cell-mediated antigen-specific immunotherapy in a mouse model of cervical cancer
Dylan Daniel1, Christopher Chiu, Enrico Giraudo
1Department of Biochemistry, Diabetes Center and Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143-0534, USA.
Abstract:
A major agenda for tumor immunology is the generation of specific immune responses leading to the destruction of incipient and frank neoplasia. In this report, we show that a novel HPV16 E7 fusion protein can produce objective therapeutic responses against incipient cervical cancer in genetically engineered mice that express in the cervix the HPV16 early region genes implicated as causative agents in human cervical cancer. Although nonresponsive toward the HPV16 E7 oncoprotein in the CD8+ T-cell compartment by virtue of MHC haplotype, the mice were capable of mounting an induced CD4+ T-cell response against E7, and in addition developed spontaneous anti-E7 antibodies. HPV16/CD4-/- mice showed increased tumor burden indicative of CD4-mediated immune surveillance. Seeking to enhance the CD4 response, we immunized mice bearing incipient cervical cancer with a recombinant protein fusing E7 with a mycobacterial heat shock protein. The incidences of cervical carcinoma and of high-grade dysplasia (CIN 3) were consequently reduced by comparison to control mice. Thus, an HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.
Insights
A novel HPV16 E7 fusion protein demonstrated therapeutic responses against incipient cervical cancer in mice. This immunotherapy approach shows promise for preventing and treating human cervical cancer.
Area of Science:
- Tumor immunology
- Oncology
- Vaccine development
Background:
- Tumor immunology aims to generate immune responses for neoplasia destruction.
- Human papillomavirus type 16 (HPV16) early region genes are causative agents in human cervical cancer.
Purpose of the Study:
- To investigate the therapeutic potential of a novel HPV16 E7 fusion protein against incipient cervical cancer.
- To evaluate the role of CD4+ T-cell responses in immune surveillance against cervical cancer.
Main Methods:
- Genetically engineered mice expressing HPV16 early region genes were used.
- Mice were immunized with a recombinant HPV16 E7 fusion protein.
- Immune responses (CD4+ T-cells, antibodies) and tumor burden were assessed.
Main Results:
- The HPV16 E7 fusion protein induced therapeutic responses against incipient cervical cancer.
- Mice mounted CD4+ T-cell responses and developed anti-E7 antibodies.
- CD4+ T-cell deficiency led to increased tumor burden, indicating immune surveillance.
- Immunization with an E7-mycobacterial heat shock protein fusion reduced cervical carcinoma and CIN 3 incidences.
Conclusions:
- An HPV16 E7 immunogen can elicit therapeutic immune responses against cervical cancer.
- CD4+ T-cells play a crucial role in immune surveillance against HPV-induced cervical cancer.
- This HPV16 E7 immunogen holds promise for noninvasive treatment and prevention of human cervical cancer.
