Submitted November 24, 2008
Accepted January 22, 2009
Depletion of CD4 T cells enhances immunotherapy for neuroblastoma after syngeneic HSCT but compromises development of anti-tumor immune memory
Weiqing Jing, Jill A. Gershan, and Bryon D. Johnson*
Department of Pediatrics, Section of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI, United States
The Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI, United States
* Corresponding author; email: bjohnson{at}mcw.edu.
High-risk neuroblastoma remains a clinically challenging disease. Here, we report that a multi-faceted immunotherapeutic approach including syngeneic hematopoietic stem cell transplantation (HSCT), adoptive transfer of "sensitized" T cells (from syngeneic donors vaccinated to tumor antigens), and early post-transplant tumor vaccination can effectively treat mice with established neuroblastoma. Vaccination was an important component of this immunotherapy, as it resulted in enhanced and prolonged tumor-specific CD8 T cell activity and improved anti-tumor efficacy. Surprisingly, CD4 cell depletion of mice given sensitized T cells resulted in better tumor-free survival which was associated with an early increased expansion of CD8 T cells with an effector phenotype, increased numbers of tumor-reactive CD8 T cells, and increased tumor infiltration by CD8 T cells. However, in the absence of CD4 T cells, development of long-term tumor immunity (memory) was severely compromised as reflected by diminished CD8 T cell recall responses and an inability to resist tumor re-challenge in vivo. Based on these results, a major challenge with this immunotherapeutic approach is how to obtain the "ideal" initial anti-tumor response but still preserve anti-tumor immune memory. These data suggest that identification and selective depletion of immune inhibitory CD4 T cells may be a strategy to enhance early anti-tumor immunity and induce a long-lasting tumor response following HSCT.
