Balancing Pro- and Anti-Inflammatory Signals for Effective Immunotherapy in the Post- Hematopoietic Stem Cell Transplant and Solid Tumor Settings

Taylor, Nicholas

Balancing Pro- and Anti-Inflammatory Signals for Effective Immunotherapy in the Post- Hematopoietic Stem Cell Transplant and Solid Tumor Settings

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March 19, 2019

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Taylor, Nicholas
- Affiliation: School of Medicine, Department of Microbiology and Immunology

Abstract

The immune system maintains a balance of activating and suppressive signals in order to promote homeostasis. However, diseases may arise when errant signals on either side of the scale perturb this delicate balance. In the work presented here, the importance of this equilibrium is demonstrated using two disease models, in which opposite effects are desired for proper treatment. Acute graft-versus-host disease (GvHD) is the result of donor T cell activation to host antigen presenting cells (APCs) and target organ damage following allogeneic hematopoietic stem cell transplant (HSCT). Conversely, as tumors grow, they evolve multiple mechanisms to evade recognition by, and suppress activation of, the immune system. In order to study the differences in proper treatment of these diseases, this work focused on three projects related to effective immunotherapy. Here, we show that donor transplanted conventional T cells (Tcons) become activated by host APCs 20 – 24 hours after transplant. Endogenous Treg cells interrupt the cell-cell interactions between Tcon and APC and downregulate co-stimulatory molecules expressed by APCs, decreasing Tcon activation. Inducible Treg cells have the same effect on Tcon activation, giving promise to Treg transplant as a viable therapy to prevent Tcon activation following HSCT. We also show that Coronin 1A, an actin-associated protein, is critical for Tcon migration from secondary lymphoid tissue (SLT), where they are activated, to target organs, where they cause damage. T cells deficient in Coronin 1A demonstrate delayed entry into, and impaired egress from, SLT following HSCT, as well as decreased NF-κB signaling. Therefore, if preventing Tcon activation is not feasible, targeting the actin cytoskeleton and the NF-κB pathway may be useful to prevent migration and development of target organ damage. Finally, we show that claudin-low breast cancers are heavily infiltrated with immune cells. However, these cells are predominantly immunosuppressive Treg cells that prevent the development of an anti-tumor response. Multimodality therapy that depletes Treg cells and prevents their function inhibits tumor growth and increases survival. Additionally, claudin-low tumors express high levels of the chemokine CXCL12, and its inhibition may decrease Treg infiltration into the tumor.

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