Access Type

Open Access Dissertation

Date of Award

January 2025

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Heather Gibson

Abstract

Immune Checkpoint Inhibitors (ICI) have dramatically improved patient outcomes in metastatic lung cancer, metastatic melanoma, subtypes of renal cancer and others. However, despite the clinical success, most patients still fail to have a durable response. Understanding what determines response and predicting who will respond to therapy is essential to improving patient outcomes. To investigate genetic underpinnings of ICI response we utilized F1 crosses of C57Bl/6 with Diversity Outbred mice (DOB6F1) and multiple Collaborative Cross (CC) strains to identify and validate (respectively) genetic loci that associated with response to ICI. The genomic data suggested that the lactation and immunomodulatory peptide prolactin played a role in response. We demonstrated that in C57Bl/6 mice prolactin can be used to augment ICI response. During studies investigating genetic underpinnings of response, we observed several tumors with a dramatic delay in tumor development after cessation of ICI therapy. Transcriptomic analysis of late onset tumors suggested that IFNγ, despite being necessary for a robust immune response, was playing a role in acquired resistance to ICI. We utilized a responding strain of CC mice to investigate whether a short treatment of B16 cells with IFNγ prior to implantation results in a more ICI resistant tumor. We observed inconsistent results suggesting IFNγ plays a nuanced role in anti-tumor immune responses. This is consistent with published literature that IFNγ has both pro and anti-tumor effects. We also sought to further develop a positron emission tomography (PET) tracer targeting IFNγ as a non-invasive method to monitor or predict response to ICI. We demonstrated that our PET tracer has significantly higher tumor uptake in mice treated with ICI, and that tumor tracer uptake correlates to treatment outcome. Since IFNγ is an important component of a normal immune response, we also demonstrated that at the imaging dose we do not have a detrimental impact on ICI outcome. This work demonstrates that heritable genetic information contributes to response to ICI, and that a PET tracer to IFNγ can predict response to ICI in a mouse model. Additionally, we generated murine models that can be used to improve rigor in tumor immunology.

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