CD40 Ligation Enhanced Naïve Tumor Antigen Specific CD8+T Cell Responses in Spontaneous Osteosarcoma Model

Abstract

Introduction: The 501 transgenic mice express the transforming T antigen (Tag) of SV40 virus causing spontaneous Tag expression in bone and salivary gland of mice. T ag expression as a self‐antigen in osteosarcoma mice leads to progressive loss of CTL responses to T ag epitopes.Objective: 1.To determine the fate of naïve TCR‐I cells in tumor bearing osteosarcoma mice that express T antigen as a tumor antigen. 2. The effect of CD40 ligation on the above response.Experiment: T antigen epitope I‐specific CD8+ T cells from Tcell receptor transgenic mice (TCR‐I cells) were transferred into tumor‐bearing 501mice or syngeneic normal C57BL/6 mice. Agonistic anti‐CD40 was given day before and day after adoptive transfer(AT), seven days later spleens and cervical lymphnodes, tumors and salivary glands were analyzed for Interferon‐γ, epitope‐1 specific tetramer, T cell infiltration, and apoptotic TUNEL staining.Results: 1) TCR‐I cells expand systemically and acquire effector function 2) Tumor specific CD8+T cell responses are aepitope‐I specific. 3) CD40 ligation enhanced TCR‐I cell proliferate. 4) In tumor‐bearing hosts TCR‐I cells proved capable of lysing 100% of target cells in vivo. 5) TCR‐I cells infiltrates salivary gland and tumor and enhanced with CD40 ligation. 6) CD40 ligation enhanced anti tumor activity detected by apoptosis using TUNEL.Conclusion: T ag expressed as a tumor antigen in osteosarcomas mice is strongly immunogenic. CD40 ligation enhanced responses to T‐ag as measured by TCR‐I proliferation, activation, migration into tumors and antitumor cell cytotoxicity.