Depletion of CD4 T cells enhances immunotherapy for neuroblastoma after syngeneic HSCT but compromises development of antitumor immune memory. Blood 2009 Apr 30;113(18):4449-57
Date
02/03/2009Pubmed ID
19182203Pubmed Central ID
PMC2676098DOI
10.1182/blood-2008-11-190827Scopus ID
2-s2.0-66149140993 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
High-risk neuroblastoma remains a clinically challenging disease. Here, we report that a multifaceted immunotherapeutic approach including syngeneic hematopoietic stem cell transplantation (HSCT), adoptive transfer of sensitized T cells (from syngeneic donors vaccinated to tumor antigens), and early posttransplantation 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 antitumor 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 rechallenge in vivo. Based on these results, a major challenge with this immunotherapeutic approach is how to obtain the ideal initial antitumor response but still preserve antitumor immune memory. These data suggest that identification and selective depletion of immune inhibitory CD4 T cells may be a strategy to enhance early antitumor immunity and induce a long-lasting tumor response after HSCT.
Author List
Jing W, Gershan JA, Johnson BDAuthor
Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cancer Vaccines
Enzyme-Linked Immunosorbent Assay
Hematopoietic Stem Cell Transplantation
Immunoenzyme Techniques
Immunologic Memory
Immunotherapy
Immunotherapy, Adoptive
Interferon-gamma
Lymphocyte Depletion
Mice
Mice, Inbred A
Myeloablative Agonists
Neuroblastoma
Phenotype
Spleen
Survival Rate
T-Lymphocytes, Regulatory
Transplantation, Isogeneic
Vaccination
