The long term of these studies is to understand and target the immunosuppressive activity of leukocytes with phenotypic attributes of inflammatory dendritic cells (DCs) that accumulate at tumor beds. This proposal focuses on elucidating and targeting the mechanisms of inhibition of ?? T cells by members of the butyrophilin family overexpressed in regulatory DCs and macrophages in ovarian cancer. Key findings for the ongoing grant have been: 1) The demonstration that novel antibodies targeting BTN3A1/2/1 rescue ?? T cells from butyrophilin- mediated suppression; 2) the identification of members of the TCR complex and receptor phosphatases that co-IP with BTN3A1; and 3) the finding that BTN3A1/2/3 are universally overexpressed in inflammatory DCs and other myeloid cells in ovarian cancer. Based on these and other findings, our central hypothesis is that BTN3A1 inhibits tumor-reactive T cells by engaging a multimeric CD45 phosphatase:CD3:TCR complex, which antagonizes phosphorylation-dependent TCR signal transduction by increasing the density of CD45 at the TCR network. In contrast, antibody-induced conformational changes in BTN3A1 elicit the activation of V?9V?2 T cells. Accordingly, our Specific Aims are:
In Specific Aim 1, we will determine the anti-tumor effectiveness of targeting human BTN3A1 in vivo in tumor-bearing hosts.
In Specific Aim 2, we will elucidate the molecular mechanism of T cell inhibition mediated by BTN3A1, based on the identification of a multimeric complex that co-IPs with BTN3A1.
In Specific Aim 3, define the mechanism of BTN3A1 deregulation at tumor beds. Our work could exert a profound effect in the field by elucidating a novel targetable immune checkpoint inhibitory pathway mediated by butyrophilins universally overexpressed in ovarian cancer. This mechanistic rationale will pave the way for a novel generation of immunotherapies that could benefit patients currently resistant to established immune checkpoint inhibitors, which may be applicable other lethal tumors and could be relevant for other ?orphan? B7 ligands.

Public Health Relevance

Despite its devastating prognosis, ovarian cancer is an immunogenic disease where the presence of organized lymphoid structures containing complex immune cell populations is associated with better outcome. The proposed studies will exert a profound effect in the field by elucidating and targeting a novel immunosuppressive pathway in ovarian cancer. This mechanistic understanding could lead to optimized interventions aimed to neutralize butyrophilins as a novel immunotherapy, thus providing a significant advance towards the goal of personalized Medicine and the cure of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124515-16
Application #
10116969
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2007-07-01
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
16
Fiscal Year
2021
Total Cost
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Perales-Puchalt, Alfredo; Perez-Sanz, Jairo; Payne, Kyle K et al. (2018) Frontline Science: Microbiota reconstitution restores intestinal integrity after cisplatin therapy. J Leukoc Biol 103:799-805
Saglam, Ozlen; Conejo-Garcia, Jose (2018) PD-1/PD-L1 immune checkpoint inhibitors in advanced cervical cancer. Integr Cancer Sci Ther 5:
Perales-Puchalt, Alfredo; Svoronos, Nikolaos; Rutkowski, Melanie R et al. (2017) Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target. Clin Cancer Res 23:441-453
Conejo-Garcia, Jose R; Payne, Kyle K; Svoronos, Nikolaos (2017) Estrogens drive myeloid-derived suppressor cell accumulation. Oncoscience 4:5-6
Svoronos, Nikolaos; Perales-Puchalt, Alfredo; Allegrezza, Michael J et al. (2017) Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Suppressor Cells. Cancer Discov 7:72-85
Stephen, Tom L; Payne, Kyle K; Chaurio, Ricardo A et al. (2017) SATB1 Expression Governs Epigenetic Repression of PD-1 in Tumor-Reactive T Cells. Immunity 46:51-64
Bitler, Benjamin G; Wu, Shuai; Park, Pyoung Hwa et al. (2017) ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol 19:962-973
Yokoyama, Yuhki; Zhu, Hengrui; Lee, Jeong Heon et al. (2016) BET Inhibitors Suppress ALDH Activity by Targeting ALDH1A1 Super-Enhancer in Ovarian Cancer. Cancer Res 76:6320-6330
Zhu, Hengrui; Bengsch, Fee; Svoronos, Nikolaos et al. (2016) BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression. Cell Rep 16:2829-2837
Allegrezza, Michael J; Rutkowski, Melanie R; Stephen, Tom L et al. (2016) Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. Cancer Res 76:6253-6265

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