Therapeutic immunization and local low‐dose tumor irradiation, a reinforcing combination

• Published in: International journal of cancer 2014-02, Vol.134 (4), p.859-872
• Main Authors: Draghiciu, Oana, Walczak, Mateusz, Hoogeboom, Baukje Nynke, Franken, Kees L.M.C., Melief, Kees J.M., Nijman, Hans W., Daemen, Toos
• Format: Article
• Language: English
• Subjects: Animals; Antigen Presentation; Antigens; Biological and medical sciences; Blotting, Western; Cancer; cancer vaccine; CD8-Positive T-Lymphocytes - immunology; Cell Proliferation; chemokines; Chemokines - metabolism; Combined Modality Therapy; Female; Flow Cytometry; Human papillomavirus; Human papillomavirus 16; Humans; Immunization; Immunoenzyme Techniques; Immunotherapy; local low‐dose tumor irradiation; Lymphocytes; Medical research; Medical sciences; Mice; Mice, Inbred C57BL; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); myeloid‐derived suppressor cells; Neoplasms, Experimental - immunology; Neoplasms, Experimental - prevention & control; Neoplasms, Experimental - virology; Oncogene Proteins, Viral - immunology; Oncogene Proteins, Viral - metabolism; Papillomaviridae - immunology; Papillomavirus E7 Proteins - immunology; Papillomavirus E7 Proteins - metabolism; Papillomavirus Infections - immunology; Papillomavirus Infections - prevention & control; Papillomavirus Infections - virology; Radiation Dosage; Real-Time Polymerase Chain Reaction; Repressor Proteins - immunology; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Semliki Forest virus; Semliki forest virus - physiology; T-Lymphocytes, Cytotoxic - immunology; Tumors; Whole-Body Irradiation
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28418

Therapeutic cancer vaccines show promise in preclinical studies, yet their clinical efficacy is limited. Increased recruitment of immune cells into tumors and suppression of the immune suppressive tumor environment are critical components toward effective cancer immunotherapies. Here, we report how local low‐dose irradiation, alone or with a therapeutic immunization based on Semliki Forest virus (SFV) against human papillomavirus (HPV)‐related cancer, influences these immune mechanisms. We first demonstrated that immunization with SFVeE6,7 or SFVeOVA, replicon particles expressing either HPV16 E6/E7 or ovalbumin, resulted in an antigen‐specific migration of CD8+ T cells into HPV‐ and OVA‐specific tumors. Local low‐dose tumor irradiation alone resulted in a 2‐fold increase of intratumoral CD8+ T cells. When 14 Gy irradiation was combined with immunization, intratumoral numbers of CD8+ T cells increased 10‐fold and the number of CD8+ T cells specific for the E7‐ epitope increased more than 20‐fold. Irradiation alone however also increased the number of intratumoral myeloid‐derived suppressor cells (MDSCs) 3.5‐fold. Importantly, this number did not further increase when combined with immunization. As a result, the ratio of antigen‐specific CD8+ T cells and MDSCs in tumors increased up to 85‐fold compared to the control. We furthermore demonstrated that following irradiation CCR2 and CCL2, CXCR6 and CCL16, chemokines and ligands involved in tumor homing of immune cells, were significantly up regulated. This study demonstrates that local low‐dose tumor irradiation influences the intratumoral immune population induced by SFVeE6,7 immunization by a strong increase in the ratio of antitumoral to immune suppressive cells, thus changing the intratumoral immune balance in favor of antitumor activity. What's new? Cancer immunotherapy often fails because of the immunosuppressive environment of the tumor and the lack of infiltration with antigen‐specific T cells. This study demonstrates that low‐dose tumor irradiation combined with a cancer vaccine can change the intratumoral immune balance in favor of antitumor immune activation. Therapeutic immununization of mice with a Semliki Forest virus‐based vector expressing human papilloma virus E6/E7 oncoproteins resulted in an 85‐fold increase in the ratio of antitumoral CD8+ T cells to immune suppressive myeloid‐derived suppressor cells at the tumor site. This raises the hope that a combination regimen might be a promising s