Author ORCID Identifier

0000-0002-1559-5639

Date of Graduation

4-2023

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Mark David Pagel, PhD

Committee Member

Pratip Bhattacharya, PhD

Committee Member

Daniel Frigo, PhD

Committee Member

Jin Seon Im, MD PhD

Committee Member

Jagannadha Sastry, PhD

Abstract

Unregulated cell division is a hallmark of cancer. The high metabolic needs of the tumor cells result in nutrient depletion and produce a hostile tumor microenvironment (TME) for antitumor immune cells, protecting the tumor from immune cell-mediated control and immunotherapy. Two of these environmental factors, acidosis and hypoxia, are commonly found in solid cancers. In my thesis, I posited that modulation of tumor acidosis and hypoxia can serve as biomarkers by indicating immunogenicity and tumor sensitivity to immune checkpoint blockade (ICB) as monitored using molecular imaging. Esomeprazole was found to promote tumor immunogenicity and induce tumor control when used to prime tumors one day before beginning ICB treatment. Using acido-Chemical Exchange Saturation Transfer Magnetic Resonance Imaging (acidoCEST MRI), pHe of 4T1 tumors after esomeprazole can predict response to combination therapy, as indicated by increased T cell activation. However, the change in B16-F10 pHe after esomeprazole predicts response to combination therapy, whose increase is compensated by increased myeloid cell infiltration. Myo-inositol trispyrophosphate (ITPP), increases oxygen release into the TME of CT26 and 4T1 tumors, increasing tumor immunogenicity and potentiating ICB tumor control. Tumor control using ITPP and ICB can be predicted using Multispectral Optoacoustic Tomography (MSOT) to measure oxygen saturation (SO2). This effect corresponds to increased intratumoral frequencies of CD8+ and CD4+FoxP3- effector T cells (Teffs) and progenitor Teff subsets. My work shows that molecular imaging can detect the priming of tumors by metabolic modulation, which translates into the ability to stratify patients into responders and non-responders of ICB.

Keywords

Immune checkpoint blockade, cancer immunotherapy, acido-Chemical Exchange Saturation Transfer Magnetic Resonance Imaging, Multispectral Optoacoustic Tomography, tumor acidity, tumor hypoxia, tumor biomarkers

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