Understanding and Targeting The Immunosuppressive Tumor Microenvironment

<p>Immune checkpoint inhibitors (ICIs), such as anti-PD1/PD-L1 and anti-CTLA-4, have shown impressive antitumor efficacy by improving the activity of T cells. While these inhibitors work in many patients with various cancer types, they have minimal or no effect in many more patients. Mounting evidence indicates that, besides current known immune checkpoints, other immunosuppressive components in the tumor microenvironment (TME) need to be targeted to elicit the full immune responses.</p> <p>Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immunosuppressive myeloid cells that are involved in cancer progression and therapeutic resistance. In this work, we demonstrated the essential role of MDSCs in PTEN-deficient prostate cancer (PCa). We revealed that MDSC recruitment can be regulated by CHD1-mediated IL6 secretion in PTEN- deficient PCa cells. Targeting the CHD1/IL-6 axis significantly decreased MDSC infiltration in TME and improved the efficacy of ICIs in multiple PTEN-deficient PCa mouse models.</p> <p>Another important aspect associated with the discrepancy in ICI response is that other immune checkpoints are operating in non-responsive tumors. BTN2A2 is a surface molecule that shares a lot of structural similarities with PD-L1. In this work, we demonstrated that BTN2A2 is a novel immune inhibitory ligand that can be targeted to improve T cell activity. It is overexpressed in multiple cancers and has been detected in various types of immune cells, including regulatory T cells, exhausted T cells, and immunoregulatory dendritic cells. Functionally, BTN2A2 inhibited proliferation and activation of human T cells; overexpressing BTN2A2 promoted tumor growth in immunocompetent mice but not in immunocompromised mice. Based on this, we developed and characterized monoclonal antibodies against human BTN2A2. We showed that anti-BTN2A2 prevents the BTN2A2-mediated inhibition of human T cells. </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2022

Authors dc:creator

• Cai, Li
• <p>0000-0002-2160-5055</p>

Contributors dc:contributor

• Ronald A. DePinho
• Mikhail G. Kolonin
• Lawrence Kwong

• immunotherapy
• prostate cancer
• MDSC
• immune checkpoint
• Laboratory and Basic Science Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1223

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2280