Dendritic cell recovery post-lymphodepletion: a potential mechanism for anti-cancer adoptive T cell therapy and vaccination

Abstract

Adoptive transfer of autologous tumor-reactive T cells holds promise as a cancer immunotherapy. In this approach, T cells are harvested from a tumor-bearing host, expanded in vitro and infused back to the same host. Conditioning of the recipient host with a lymphodepletion regimen of chemotherapy or radiotherapy before adoptive T cell transfer has been shown to substantially improve survival and anti-tumor responses of the transferred cells. These effects are further enhanced when the adoptive T cell transfer is followed by vaccination with tumor antigens in combination with a potent immune adjuvant. Although significant progress has been made toward an understanding of the reasons underlying the beneficial effects of lymphodepletion to T cell adoptive therapy, the precise mechanisms remain poorly understood. Recent studies, including ours, would indicate a more central role for antigen presenting cells, in particular dendritic cells. Unraveling the exact role of these important cells in mediation of the beneficial effects of lymphodepletion could provide novel pathways toward the rational design of more effective anti-cancer immunotherapy. This article focuses on how the frequency, phenotype, and functions of dendritic cells are altered during the lymphopenic and recovery phases post-induction of lymphodepletion, and how they affect the anti-tumor responses of adoptively transferred T cells.

Fig. 1

Suggested phases post-CTX therapy and proposed approaches for their manipulation in vivo to benefit adoptive T cell therapy (ACT). CTX treatment induces a rapid lymphopenia for about 5 days followed by a gradual cellular recovery with a full recovery after 18–20 days of treatment. The cellular recovery is characterized by an expansion of cells with immature myeloid-derived suppressor cell (MDSC) phenotype (Gr-1⁺CD11b⁺) followed by an expansion of DCs with CD11c⁺CD11b⁺ phenotype in the peripheral blood, spleen, and liver. The expansion of DCs occurs when the expanded MDSC start to contract. Vaccination with a tumor antigen (Ag) and a potent adjuvant, such as a TLR ligand (TLRL) can activate the expanded DCs and MDSC, resulting in beneficial host microenvironment to T cell responses

Fig. 2

Proposed paradigm for DC activation post-lymphodepletion and its impact on antigen-specific responses of adoptive T cell therapy. Treatment with a lymphodepleting dose of CTX or TBI induces a rapid lymphopenia likely associated with microbial translocation due to the damage of the intestinal tract. Lymphopenia can result in elimination or an inbalance of regulatory elements, including T_reg cells and myeloid-derived suppressor cells. Microbial translocation can also result in the release of microbial products such as LPS, which leads to activation of antigen presenting cells, in particular DCs. The intensity of these events, however, decreases gradually during the recovery phase from lymphopenia, in which DCs are expanded in circulation due to mobilization of DC precursors (solid line). Adoptively transferred antigen-specific T cells (dotted line) during the lymphopenic phase can benefit from the space “niche” and the more available survival cytokines and thus show homeostatic proliferation. The proliferation of these cells is further increased if the host is also primed with a specific antigen, particularly in the presence of endogenous activated DCs. The inflammatory microenvironment created during the peak of the antigen-specific responses of donor T cells to antigen priming might result in activation of the expanded DCs during the recovery phase, and thus could slightly augment the T cell responses when the antigen boosting occurs at this time point. Addition of an inflammatory adjuvant (e.g. TLR agonist) at the time of DC surge, however, would accentuate the inflammatory microenvironment that can induce the full activation and maturation of the expanded DCs and their migration to LNs, resulting in robust antigen-specific responses of donor cells (dotted line)