Submitted September 5, 2006
Accepted January 30, 2007
Adoptive transfer of tumor-primed, in vitro activated, CD4+ T-effectors (TE) combined with CD8+ TE provides intratumoral TE proliferation and synergistic anti-tumor response
Li-Xin Wang, Suyu Shu, Mary L. Disis, and Gregory E Plautz*
Center for Surgery Research, The Cleveland Clinic Foundation, Cleveland, OH, United States
Center for Translational Medicine in Women's Health, Tumor Vaccine Group, University of Washington, Seattle, WA, United States
* Corresponding author; email: plautzg{at}ccf.org.
The importance of CD4+ Th1 cells during the effector phase of the anti-tumor response has been overshadowed by emphasis on CD8+ CTL. To determine their respective functions, we purified antigen-primed T cells from tumor-draining lymph nodes and separately activated CD4+ and CD8+ subsets in vitro. Adoptive transfer of CD4+ T effectors (TE) combined with CD8+ TE provided synergistic therapy for mice bearing subcutaneous, intracranial, or advanced pulmonary metastases. CD4+ TE augmented IFN-
production by CD8+ TE when cells were stimulated by tumor-digest containing APC. CD4+ TE infiltrated and proliferated extensively in pulmonary tumors, while also stimulating tumor antigen-specific CD8+ T cells. By contrast, CD8+ TE cells showed minimal intratumoral proliferation in the absence of CD4+ cells or when systemically transferred CD4+ cells were prevented from infiltrating pulmonary tumors by pre-treatment with pertussis toxin. Irradiation of CD4+ T cells immediately prior to adoptive transfer abrogated their intratumoral proliferation and direct anti-tumor efficacy but didn't block their capacity to stimulate intratumoral CD8+ TE proliferation or tumor regression. These results highlight the importance of cross-presentation of tumor antigens during the effector phase of immunotherapy and suggest that approaches to stimulate CD4+ TE function and boost APC cross-presentation within tumors will augment cancer immunotherapy.
