1. ¹Divison of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea
2. ²Otolaryngology/Head and Neck Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
3. ³Gynecology & Reproductive Sciences, Department of Obstetrics, Yale University School of Medicine, New Haven, Connecticut, USA
4. ⁴Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
5. ⁵Department of Obstetrics and Gynecology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
6. ⁶Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
7. ⁷Department of Molecular Microbiology and Immunology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, USA

Correspondence: T-C Wu, Department of Pathology, The Johns Hopkins University School of Medicine, CRB II Room 309, 1550 Orleans Street, Baltimore, Maryland 21231, USA. E-mail: wutc@jhmi.edu or; Tae W Kim, Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, 516 Gojan-1 Dong, Ansan-Si, Gyeonggi-Do 425-707, South Korea. E-mail: twkim0421@korea.com

The first two authors contributed equally to this work.

Received 6 August 2008; Accepted 17 October 2008; Published online 23 December 2008.

Abstract

Immune evasion is an important reason why the immune system cannot control tumor growth. To elucidate the mechanism for tumor immune evasion, we generated an immune-resistant human papillomavirus type 16 (HPV-16) E7-expressing tumor cell line by subjecting a susceptible tumor cell line to multiple rounds of in vivo immune selection with an E7-specific vaccine. Comparison of parental and immune-resistant tumors revealed that Akt is highly activated in the immune-resistant tumors. Retroviral transfer of a constitutively active form of Akt into the parental tumor significantly increased its resistance against E7-specific CD8⁺ T-cell mediated apoptosis. The observed resistance against apoptosis was found to be associated with the upregulation of antiapoptotic molecules. We also observed that intratumoral injection of an Akt inhibitor enhanced the therapeutic efficacy of E7-specific vaccine or E7-specific CD8⁺ T-cell adoptive transfer against the immune-resistant tumors. Thus, our data indicate that the activation of PI3K/Akt pathway represents a new mechanism of immune escape and has important implications for the development of a novel strategy in cancer immunotherapy against immune-resistant tumor cells.