van Mierlo Geertje J D, den Boer Annemieke Th, Medema Jan Paul, van der Voort Ellen I H, Fransen Marieke F, Offringa Rienk, Melief Cornelis J M, Toes Rene E M
Department of Immunohematology and Bloodtransfusion, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5561-6. doi: 10.1073/pnas.082107699. Epub 2002 Apr 2.
Adequate spontaneous activation of tumor-specific T lymphocytes in tumor-bearing hosts is rare, despite the expression of tumor antigens that are potentially highly immunogenic. For example, failure of the immune system to raise competent responses against established tumors expressing the human adenovirus E1A-antigen allows this tumor to grow in immunocompetent mice. We show that systemic in vivo administration of agonistic anti-CD40 antibodies into tumor-bearing mice results in tumor eradication mediated by CD8(+) T cells. Treatment resulted in a strong expansion and systemic accumulation of E1A-specific CTL and depended on CD40 expression on host cells, as the tumor was CD40(-), and therapy failed in CD40-deficient mice. Local intratumoral administration of anti-CD40 mAb is equally effective in licensing strong, systemic CTL immunity, resulting in the clearance of distant tumor nodules. Our data indicate that the immune response after cancer-host interactions can be directed toward competence, leading to the cure of established tumors merely by delivery of a CD40-dependent "license to kill" signal.
在荷瘤宿主中，尽管肿瘤抗原具有潜在的高免疫原性，但肿瘤特异性T淋巴细胞的充分自发激活却很少见。例如，免疫系统无法对表达人腺病毒E1A抗原的已建立肿瘤产生有效反应，使得这种肿瘤能够在免疫健全的小鼠体内生长。我们发现，向荷瘤小鼠体内全身性给予激动性抗CD40抗体可导致由CD8(+) T细胞介导的肿瘤根除。治疗导致E1A特异性CTL强烈扩增并在全身蓄积，且依赖于宿主细胞上的CD40表达，因为肿瘤是CD40(-)，并且在CD40缺陷小鼠中治疗失败。局部瘤内给予抗CD40单克隆抗体在激发强大的全身性CTL免疫方面同样有效，可导致远处肿瘤结节的清除。我们的数据表明，癌症与宿主相互作用后的免疫反应可以导向有效状态，仅通过传递CD40依赖性的“杀伤许可”信号就能治愈已建立的肿瘤。
