Investigating the Role of Indoleamine 2,3-Dioxygenase 1 and Transforming Growth Factor Beta 1 in Rebound Immune Suppression Following Chemotherapy in Osteosarcoma

This thesis is a culmination of current and past scientific evidence in the literature and research investigating potential immunological targets to overcome osteosarcoma (OS) metastatic disease. OS is a malignant mesenchymal neoplasm and the most common primary solid bone tumor in dogs and humans. Given biological similarities between humans and dogs, pet dogs with OS are considered a large animal model for translational cancer research, especially in the field of immuno-oncology and drug discovery. Thus, this thesis will investigate two tolerogenic components, indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta 1 (TGFβ1), as potential targets for immunotherapeutic interventions for pet dogs with OS. In this context, Chapter I will provide an overview of the literature in the field of immuno-oncology with emphasis on immune-regulatory mechanisms operative in the tumor microenvironment of canine osteosarcoma. This literature review also describes the relationship between cell death and immunological responses, including tolerogenic and immunosuppressive components in canine osteosarcoma. Moreover, potential strategies to mitigate regulatory and pro-tumorigenic responses are also reviewed in Chapter I. Chapter II investigates two potential targets in tolerogenic responses and the rebound immune suppression phenomenon. This in vitro study aimed to investigate the role of IDO1 and TGFβ1 in OS and immune cells from mice and dogs as potential targets for studies in clinically relevant metastatic OS models. We aimed to determine IDO1 enzymatic activity and potential sources of TGFβ1 in the tumor microenvironment. In addition, we also characterized the biological impacts of these players in immunocytes and inhibitory studies. Based on the results from this chapter, IDO1 and TGFβ1 serve as potential targets for immunotherapeutic interventions in OS. Chapter III describes an in vivo study using the K7M2 Balb/c model of metastatic OS and immunotherapy strategies targeting IDO1 and TGFβ1. The study reports the potential therapeutic use of Galunisertib and Epacadostat, two inhibitors of TGFβR1 and IDO1, respectively. The results show that combined treatment with Doxorubicin, Galunisertib, and Epacadostat can attenuate the development of pulmonary metastasis without causing toxicity or severely affecting systemic immunity. However, Galunisertib and Epacadostat treatments, alone or in combination with Doxorubicin, do not attenuate metastasis development. Further studies are needed to understand the immunological mechanisms underlying these benefits in a clinical setting for OS. Chapter IV concludes the thesis and discusses future directions in the field.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

VMS-Veterinary Clincial Medcne

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2023

Author dc:creator

• Passos Barbosa, Matheus Moreno

Contributors dc:contributor

• Fan, Timothy M
• Keating, Stephanie CJ
• Aldrige, Brian M

• Bone Cancer
• Canine
• Pet Dogs
• Immunotherapy
• Oncology
• Epacadostat
• Galunisertib

Statement dc:rights

• Copyright 2023 Matheus Moreno Passos Barbosa

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/120219

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F120219