Protection from tumor recurrence following adoptive immunotherapy varies with host conditioning regimen despite initial regression of autochthonous murine brain tumors

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• 作者：Eugene M. Cozza (1)
  Timothy K. Cooper (2) (3)
  Lynn R. Budgeon (3)
  Neil D. Christensen (1) (3) (4)
  Todd D. Schell (1) (4)
  
  1. Department of Microbiology and Immunology ; Penn State Hershey College of Medicine ; 500 University Drive ; H107 ; Hershey ; PA ; 17033 ; USA
  2. Department of Comparative Medicine ; Penn State Hershey College of Medicine ; Hershey ; PA ; 17033 ; USA
  3. Department of Pathology ; Penn State Hershey College of Medicine ; Hershey ; PA ; 17033 ; USA
  4. Penn State Hershey Cancer Institute ; Hershey ; PA ; 17033 ; USA
  
• 关键词：CD8+ T cell ; CD40 agonist ; Choroid plexus tumor ; SV40 T antigen transgenic mice ; Whole ; body irradiation
• 刊名：Cancer Immunology, Immunotherapy
• 出版年：2015
• 出版时间：March 2015
• 年：2015
• 卷：64
• 期：3
• 页码：325-336
• 全文大小：1,172 KB
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• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Cancer Research
  Immunology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0851

文摘

Adoptive T cell transfer (ACT) has achieved clinical success in treating established cancer, particularly in combination with lymphodepleting regimens. Our group previously demonstrated that ACT following whole-body irradiation (WBI) promotes high-level T cell accumulation, regression of established brain tumors, and long-term protection from tumor recurrence in a mouse model of SV40 T antigen-induced choroid plexus tumors. Here we asked whether an approach that can promote strong donor T-cell responses in the absence of WBI might also produce this dramatic and durable tumor elimination following ACT. Agonist anti-CD40 antibody can enhance antigen-specific CD8+ T-cell responses and has shown clinical efficacy as a monotherapy in the setting of cancer. We show that anti-CD40 conditioning promotes rapid accumulation of tumor-specific donor CD8+ T cells in the brain and regression of autochthonous T antigen-induced choroid plexus tumors, similar to WBI. Despite a significant increase in the lifespan, tumors eventually recurred in anti-CD40-conditioned mice coincident with loss of T-cell persistence from both the brain and lymphoid organs. Depletion of CD8+ T cells from the peripheral lymphoid organs of WBI-conditioned recipients failed to promote tumor recurrence, but donor cells persisted in the brains long-term in CD8-depleted mice. These results demonstrate that anti-CD40 conditioning effectively enhances ACT-mediated acute elimination of autochthonous tumors, but suggest that mechanisms associated with WBI conditioning, such as the induction of long-lived T cells, may be critical for protection from tumor recurrence.