Tumor-infiltrating lymphocytes (TILs) are found in many solid tumors in patients. Although a significant fraction of TILs recognize tumor-derived Ags, they are usually nonfunctional (tolerized), as they lack cytolytic activity and/or effector cytokine production (1
). A major objective of cancer immunotherapy is to reactivate TILs so that they can kill cancer cells. One such approach has been adoptive cell transfer (ACT), in which TILs are isolated from patients, expanded ex vivo, and reintroduced into patients. ACT has been effective in treating metastatic melanoma, achieving response rates of over 50% when combined with patient-preconditioning strategies (2
). However, a limit to the effectiveness of ACT is that activated T cells can lose their function through tumor-induced tolerance, so additional strategies are needed to help maintain the function of activated TILs in the tumor environment.
Another potential approach to induce antitumor T cell responses is through intratumoral injection of dendritic cells (DCs). DCs are specialized APCs that capture, process, and present Ags and subsequently direct T cell function (4
). Although functional mature DCs can initiate robust antitumor T cell responses, DCs acted on by tumor-derived factors are generally suppressive (5
). It is anticipated that functional DCs injected into tumors could overcome the effects of resident suppressive DCs. Indeed, intratumoral administration of either Ag-loaded or plain DCs has induced antitumor responses in transplanted tumor models in mice and rats (6
). In humans, intratumoral injection of autologous DCs induced tumor regression in 6 out of 10 patients with melanoma and breast cancer (8
). Similarly, intratumoral and intradermal administration of tumor lysate-pulsed autologous DCs promoted longer survival in patients with glioma than intradermal administration alone (9
Despite the successes of inducing antitumor immunity and tumor regression, it has not been directly demonstrated whether intratumoral injection of DCs can reactivate persisting TILs in situ. In previous studies with intratumoral DC administration, antitumor immunity has generally been evaluated through gross measurements of tumor regression, with minimal analysis of the function of tumor-reactive T cells in the tumor tissue. In studies that analyzed antitumor T cell immunity, CD8 and/or CD4 T cells from the spleens, lymph nodes, or peripheral blood of tumor-bearing animals were assayed for Ag-specific cytolytic activity and/or effector cytokine production. However, the function of tumor-reactive T cells in the periphery can be significantly different from that in the tumor tissue itself (10
). Furthermore, most previous studies used transplanted tumors, which may not capture the essential properties of TILs found in spontaneous primary tumors. Thus, although intratumoral DC administration has been shown to enhance antitumor immunity, it is not clear whether TILs can be directly reactivated by functional DCs within autochthonous tumors or whether intratumoral injection of DCs can sustain the function of effector T cells in the tumor tissue during ACT.
In an autochthonous prostate cancer model, we show in this study that intratumoral injection of ex vivo-matured, Ag-loaded DCs can both delay the tolerization of tumor-infiltrating effector T cells and reactivate persisting tolerized T cells in the tumor tissue. These findings provide new strategies to augment ACT as well as to reactivate tolerized TILs in situ for cancer immunotherapy.