Skip to Main Content
 

Global Search Box

 
 
 

ETD Abstract Container

Abstract Header

Immunogenic Shift of Arginine Metabolism to Reprogram Tumor-Associated Macrophages in Breast Cancer

Fernando, Veani Roshale
http://orcid.org/0000-0002-4759-653X
http://rave.ohiolink.edu/etdc/view?acc_num=mco1687738862386368

Abstract Details

2023, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Cancer Biology).
Immunotherapy at best yields moderate responses in breast cancer, despite its success in other cancer types. Such therapeutic inefficacy is instigated by the immunosuppressive nature of the breast Tumor Microenvironment (TME). Tumor-Associated Macrophages (TAMs) harbored within the TME, predominantly contribute to this hostile milieu by manifesting an immunosuppressive, pro-tumorigenic M2-TAMs while down-modulating the immunostimulatory, anti-tumorigenic M1-TAMs. Therefore, reprogramming M2-TAMs to M1 could induce an immunogenic shift in breast TME and increase the efficacy of immunotherapeutics. Switching gears from current toxicogenic cytokine-mediated reprogramming methods, we aimed to target the l-arginine metabolism in TAMs for immunogenic reprogramming. As M2-TAMs are deficient in the synthesis of tetrahydrobiopterin (BH4), the co-factor of nitric oxide synthase (NOS), we hypothesized that supplementing Sepiapterin (SEP), the precursor of BH4 would redirect arginine metabolism from polyamine (PA) to nitric oxide production (NO), reprogram to M1-TAMs and increase anti-tumorigenicity. We recently reported that SEP treatment redirected arginine metabolism in M2-TAMs towards NO pathway and induced their phenotypic conversion to M1 type. In the present study, we demonstrate that SEP treatment functionally reprograms M2-TAMs to M1-TAMs, significantly elevate their immunogenic responses including activation of cytotoxic T cells and induce immunogenic cell death (ICD), a distinctive form of apoptosis, in HER2+ breast cancer cells. Consistently, SEP treatment suppresses HER2+ mammary tumor growth in vivo and enhances immunostimulation in breast TME. This study provides new evidence that SEP-mediated immunometabolic reprogramming induces an immunogenic shift in the HER2+ breast TME and can be utilized as a novel immunotherapeutic strategy.
Ivana de la Serna (Committee Chair)
Saori Furuta (Committee Member)
Heather Conti (Committee Member)
Kandace Williams (Committee Member)
Kam Yeung (Committee Member)
174 p.
Biomedical Research; Oncology
Tumor-associated macrophages, Metabolic reprogramming, Immunotherapy, Breast Cancer

Recommended Citations

Citations

  • Fernando, V. R. (2023). Immunogenic Shift of Arginine Metabolism to Reprogram Tumor-Associated Macrophages in Breast Cancer [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1687738862386368

    APA Style (7th edition)

  • Fernando, Veani. Immunogenic Shift of Arginine Metabolism to Reprogram Tumor-Associated Macrophages in Breast Cancer. 2023. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1687738862386368.

    MLA Style (8th edition)

  • Fernando, Veani. "Immunogenic Shift of Arginine Metabolism to Reprogram Tumor-Associated Macrophages in Breast Cancer." Doctoral dissertation, University of Toledo, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=mco1687738862386368

    Chicago Manual of Style (17th edition)

mco1687738862386368
77
© 2023, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.
Release 3.2.12