RESUMO
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.
Assuntos
Imunoterapia , Neoplasias Experimentais/prevenção & controle , Papillomaviridae/imunologia , Infecções por Papillomavirus/prevenção & controle , Vírus da Floresta de Semliki/fisiologia , Linfócitos T Citotóxicos/imunologia , Irradiação Corporal Total , Animais , Apresentação de Antígeno , Western Blotting , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células , Quimiocinas/metabolismo , Terapia Combinada , Feminino , Citometria de Fluxo , Humanos , Imunização , Técnicas Imunoenzimáticas , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/virologia , Proteínas Oncogênicas Virais/imunologia , Proteínas Oncogênicas Virais/metabolismo , Proteínas E7 de Papillomavirus/imunologia , Proteínas E7 de Papillomavirus/metabolismo , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , RNA Mensageiro/genética , Doses de Radiação , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Repressoras/imunologia , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Ovarian cancer vaccines are one of the new treatment strategies under investigation in epithelial ovarian cancer. This article discusses the results of different immunization strategies, points out potential pitfalls in study designs and provides possible solutions for augmentation of clinical efficacy. Most ovarian cancer vaccines have not yet evolved beyond Phase I/II studies, which do not primarily evaluate clinical efficacy. Although different approaches of antigen-specific immunization generally result in antigen-specific immune responses, clinical benefit is not consistently observed. Based on the currently available results, we emphasize the necessity of multimodal treatment of ovarian cancer, combining classical cytoreductive surgery, (neo)adjuvant chemotherapy, immunotherapy and/or targeted therapy.