Adoptive transfer of tumor-primed, in vitro–activated, CD4+ T effector cells (TEs) combined with CD8+ TEs provides intratumoral TE proliferation and synergistic antitumor response

Abstract

The importance of CD4⁺ Th1 cells during the effector phase of the antitumor response has been overshadowed by emphasis on CD8⁺ cytotoxic T lymphocytes (CTLs). 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 effector cells (T_Es) combined with CD8⁺ T_Es provided synergistic therapy for mice bearing subcutaneous, intracranial, or advanced pulmonary metastases. CD4⁺ T_Es augmented IFN-γ production by CD8⁺ T_Es when cells were stimulated by tumor digest–containing antigen-presenting cells (APCs). CD4⁺ T_Es infiltrated and proliferated extensively in pulmonary tumors, while also stimulating tumor antigen–specific CD8⁺ T cells. By contrast, CD8⁺ T_Es showed minimal intratumoral proliferation in the absence of CD4⁺ cells or when systemically transferred CD4⁺ cells were prevented from infiltrating pulmonary tumors by pretreatment with pertussis toxin. Irradiation of CD4⁺ T cells immediately prior to adoptive transfer abrogated their intratumoral proliferation and direct antitumor efficacy but did not block their capacity to stimulate intratumoral CD8⁺ T_E 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⁺ T_E function and boost APC cross-presentation within tumors will augment cancer immunotherapy.