Doctor of Philosophy (Ph.D.)
Degree Granting Department
Biology (Cell Biology, Microbiology, Molecular Biology)
Shari Pilon-Thomas, Ph.D.
Daniel Abate-Daga, Ph.D.
Amer Beg, Ph.D.
Paulo Rodriguez, Ph.D.
Ken Wright, Ph.D.
Suzanne Ostrand-Rosenberg, Ph.D.
41BB, MDSCs, hematopoiesis, tumor infiltrating lymphocytes, T cells
Adoptive T cell therapy (ACT) in combination with lymphodepleting chemotherapy is an effective strategy to induce the eradication of tumors, providing long-term regression in cancer patients. However, only a minority of patients that receive ACT with tumor infiltrating lymphocytes (TILs) exhibit durable benefit. Thus, there is an urgent need to define strategies that potentiate anti-tumor activity conducted by adoptively transferred T cells. In these studies, we aimed to identify novel strategies to enhance the therapeutic efficacy of ACT. Accordingly, we describe the disparate roles of myeloid cells in the context of ACT characterized by the augmentation of TIL proliferation in the presence of 41BB-mediated co-stimulation and the dampening of anti-tumor immunity orchestrated by myeloid derived suppressor cells (MDSCs).
The efficient expansion of T cells is a critical aspect of ACT, which is aided by culturing tumors and TILs in IL-2 and 41BB agonistic antibodies. However, the impact of 41BB-mediated co-stimulation conducted by constituent myeloid cells within tumors on the expansion of TILs is unclear. Here, we describe that the intratumoral administration of 41BB agonistic antibodies led to increases in CD8 T cell infiltration followed by tumor regression in murine models. We found that granulocytes and monocytes rapidly replaced macrophages and dendritic cells in tumors following administration of anti-41BB antibodies. Overall, myeloid cells from anti-41BB treated tumors had an improved capacity to stimulate T cells in comparison to myeloid cells from control treated tumors. In human co-culture systems, we demonstrated that the agonism of the 41BB-41BBL axis enhanced co-stimulatory signals and effector functions among antigen presenting cells and autologous TILs. Thus, myeloid-mediated co-stimulation is a critical factor in potentiating the proliferation of TILs and their anti-tumor activity.
Despite that lymphodepleting regimens condition the host for optimal engraftment and expansion of adoptively transferred T cells, lymphodepletion concomitantly promotes immunosuppression during the course of endogenous immune recovery. Here, we have identified that lymphodepleting chemotherapy initiates the mobilization of hematopoietic progenitor cells that differentiate to immunosuppressive myeloid cells, leading to a dramatic increase of peripheral MDSCs. In melanoma and lung cancer patients, MDSCs rapidly expanded in the periphery within one week after completion of a lymphodepleting regimen and infusion of autologous tumor infiltrating lymphocytes (TIL). This expansion was associated with disease progression, poor survival, and reduced TIL persistence in melanoma patients. We demonstrated that the IL-6 driven differentiation of mobilized hematopoietic progenitor cells promoted the survival and immunosuppressive capacity of post-lymphodepletion MDSCs. Furthermore, the genetic abrogation or therapeutic inhibition of IL-6 in mouse models enhanced host survival and reduced tumor growth in mice that received ACT. Thus, the expansion of MDSCs in response to lymphodepleting chemotherapy may contribute to ACT failure and targeting myeloid-mediated immunosuppression may support anti-tumor immune responses.
Collectively, we demonstrate that exploiting the immunostimulatory capacity of myeloid cells and the curtailment of myeloid-mediated immunosuppression are strategies that can augment the expansion and anti-tumor activity of TILs. The novel mechanistic insights of these studies highlight the importance of modulating myeloid cells to promote the therapeutic efficacy of ACT.
Scholar Commons Citation
Innamarato, Pasquale Patrick, "The Impact of Myeloid-Mediated Co-Stimulation and Immunosuppression on the Anti-Tumor Efficacy of Adoptive T cell Therapy" (2020). USF Tampa Graduate Theses and Dissertations.