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Tumor-Specific CD4⁺ T Lymphocytes from Cancer Patients Are Required for Optimal Induction of Cytotoxic T Cells Against the Autologous Tumor

Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens, Greece

This study focuses on the specific CD4⁺ T cell requirement for optimal induction of cytotoxicity against MHC class II negative autologous tumors (AuTu) collected from patients with various types of cancer at advanced stages. CD4⁺ T cells were induced in cultures of cancer patients’ malignant effusion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant IL-7. Tumor-specific CD4⁺ T cells did not directly recognize the AuTu cells, but there was an MHC class II-restricted cross-priming by autologous dendritic cells (DCs), used as APC. CD8⁺ CTL, also induced during the MLTC, lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC class I-restricted manner. Removal of CD4⁺ T cells or DCs from the MLTC drastically reduced the CD8⁺ CTL-mediated cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with autologous CD4⁺ T cells were able, in the absence of CD4⁺ T cells, to stimulate CD8⁺ T cells to lyse autologous tumor targets. Such activated CD8⁺ T cells produced IL-2, IFN-, TNF-, and GM-CSF. The process of the activation of AWE-pulsed DCs by CD4⁺ T cells could be inhibited with anti-CD40 ligand mAb. Moreover, the role of CD4⁺ T cells in activating AWE-pulsed DCs was undertaken by anti-CD40 mAb. Our data demonstrate for the first time in patients with metastatic cancer the essential role of CD4⁺ Th cell-activated DCs for optimal CD8⁺ T cell-mediated killing of autologous tumors and provide the basis for the design of novel protocols in cellular adoptive immunotherapy of cancer, utilizing synthetic peptides capable of inducing T cell help in vivo.