Therapeutic immunization and local low-dose tumor irradiation, a reinforcing combination.
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.
Department of Medical Microbiology, Molecular Virology Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Oana
O
Draghiciu
Mateusz
M
Walczak
Baukje Nynke
BN
Hoogeboom
Kees L M C
KL
Franken
Kees J M
KJ
Melief
Hans W
HW
Nijman
Toos
T
Daemen
D000818:Animals; D017951:Antigen Presentation; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007114:Immunization; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D009856:Oncogene Proteins, Viral / Q000276:immunology / Q000378:metabolism; D027383:Papillomaviridae / Q000276:immunology*; D050725:Papillomavirus E7 Proteins / Q000276:immunology / Q000378:metabolism; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D011829:Radiation Dosage; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012672:Semliki forest virus / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014916:Whole-Body Irradiation
D018925:Chemokines; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16
Semliki Forest virus; cancer vaccine; chemokines; local low-dose tumor irradiation; myeloid-derived suppressor cells