Effective anti-neu-initiated antitumor responses require the complex role of CD4+ T cells.
OBJECTIVE
Targeting oncogenic receptors with antibodies has been thought to suppress tumor growth mainly by interrupting oncogenic signals. Recently, the essential role for adaptive immunity, and CD8(+) T cells in particular, has been established as a major factor for anti-HER2/neu-mediated tumor regression. However, the role of CD4(+) T cells is still being defined. The purpose of this study was to explore whether and to what extent CD4(+) T cells are involved in mediating the effects of anti-HER2/neu therapy.


METHODS
The role of CD4(+) T cells was examined using a transplant model of the rat HER2/neu-overexpressing cell line TUBO. Tumor-bearing mice were treated with anti-neu therapy in conjunction with CD4 depletion or CD40L blockade. The effects of CD4 depletion on the antitumor response were examined by tumor growth analysis and enzyme-linked immunospot (ELISPOT).


RESULTS
In addition to CD8(+) T cells, CD4(+) T cells are also essential for anti-neu antibody-mediated tumor regression, but B cells are not required. The role for CD4(+) cells is necessary throughout anti-neu therapy and not limited to helping CD8(+) T cells. Expression of IFN-γ is necessary for anti-neu therapy and IFN-γ induces MHC-II expression in TUBO cells promoting direct recognition by CD4(+) T cells. Furthermore, intratumoral depletion of CD4(+) T cells or blockade of the activating cell-surface protein CD40L inhibits the antitumor response.


CONCLUSIONS
This study reveals the essential role of CD4(+) T cell for anti-neu-mediated tumor regression.
Institute of Biophysics and the University of Chicago Group for Immunotherapy, Chinese Academy of Science Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Eric D
ED
Mortenson
SaeGwang
S
Park
Zhujun
Z
Jiang
Shengdian
S
Wang
Yang-Xin
YX
Fu
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*
D000906:Antibodies; D007371:Interferon-gamma; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human