Cutting Edge: Delay and Reversal of T Cell Tolerance by Intratumoral Injection of Antigen-Loaded Dendritic Cells in an Autochthonous Tumor Model

Abstract

The tumor environment exerts a powerful suppressive influence on infiltrating tumor-reactive T cells. It induces tolerance of adoptively transferred effector T cells as they enter tumors and maintains the tolerance of persisting tumor-infiltrating T cells. In an autochthonous prostate cancer model, in which tumor-reactive CD8 T cells are trackable, we demonstrate that both depletion of endogenous dendritic cells (DCs) and intratumoral injection of Ag-loaded mature DCs delayed the tolerization of tumor-infiltrating effector CD8 T cells. Intratumoral injection of Ag-loaded DCs also reactivated tolerized CD8 T cells in the tumor tissue. The observed effects lasted as long as the injected DCs persisted. These findings are consistent with a critical role of DCs in modulating T cell reactivity in the tumor environment. They also suggest new potential strategies to extend the functionality of transferred effector T cells and to restore function to tolerized tumor-infiltrating T cells for cancer immunotherapy.

Differential Requirement for CD70 and CD80/CD86 in Dendritic Cell-Mediated Activation of Tumor-Tolerized CD8 T Cells

“…The observed difference was not due to differential retention of anti-CD70 treated BMDCs within the prostate tissue as compared to control treated BMDCs (Fig. 5 E ), consistent with previous experiments with untreated BMDCs (13). These results show that CD70/CD27 interaction is required for DC-mediated delay of 2C T cell tolerance induction in the prostate tumor tissue.…”

“…3B). Previous work has shown that depletion of prostate DCs reverses 2C T cell tolerance (13). Considering that tolerance can result from pMHC presentation by DCs lacking costimulatory signals (32), these data suggest that steady-state prostate resident DCs promote T cell tolerance, perhaps through pMHC/TCR engagement without costimulation.…”

“…Despite Ag expression within the TRP-SIY prostate (11), and a population of tissue resident DCs (13), 2C T cells are tolerized within the prostate. Indeed, we show that endogenous DCs within the prostate express levels of costimulatory molecules barely above background (Fig.…”

“…In vivo cytotoxicity was performed as previously described (13). Briefly, C57BL/6 (Thy1.1 + ) splenocytes were activated on anti-CD3 coated plates in the presence of 50 U/mL IL-2 for 3 days.…”

“…The tolerized 2C T cells persist in the prostate tumor tissue (12) expressing high levels of PD-1, analogous to TILs in patients. Importantly, we have found that antigen-loaded bone marrow-derived DCs (BMDCs), when injected intraprostatically, delay the rapid tolerance induction of effector 2C T cells as they initially infiltrate the tumor tissue (13). In addition, when antigen-loaded BMDCs are injected after initial tolerance induction, they refunctionalize the persisting tolerized 2C T cells in the tumor tissue.…”