Despite its aggressiveness and scarcity of mutated neo-epitopes, multiple lines of evidence support that ovarian carcinomas are truly immunogenic3-11. Understanding the nature of those responses and their dynamics specifically in ovarian cancer will be the focus of this competitive renewal. Key experimental findings supporting this proposal have been: 1) the identification of many ovarian cancers in TCGA datasets exhibiting strong markers of T cell-mediated cytolytic activity and ZERO missense mutations or frameshifts; 2) the fact that all of these immunogenic tumors without mutated neo-antigens show re-activation of endogenous retroviruses (ERVs); and 3) the identification of a new class of chimeric neo-antigens combining exons encoded by re-activated endogenous retroviruses plus exons from nearby protein-coding genes. Based on these and other of our findings, our central hypothesis is that immunogenicity in ovarian cancer is in part driven by the re-activation of endogenous retroviruses, resulting in the generation of chimeric antigens, so that ovarian malignancies become more - not less - immunogenic as the disease progresses in an immunosuppressive environment.
In Aim 1, we will determine the role of retrovirally-driven chimeric antigens in immune protection against ovarian cancer. These results will validate the existence of a new class of tumor-specific antigens resulting from the re-activation of ERVs, which are expected to drive the immunogenicity of tumors with a limited repertoire of mutated neo-antigens.
In Aim 2, we will define the role of re-activated endogenous retroviruses in the evolution of anti-tumor immunity. Supporting our preliminary results, these data are expected to substantiate a new framework to understand the dynamics and drivers of protective immunity against ovarian cancer, based on delayed but progressive immunogenicity, largely independent of mutated neo-antigens.
In Aim 3, we will elucidate the mechanisms leading to the re-activation of ERVs in human ovarian cancer and, correspondingly, the intrinsic drivers of the immunogenicity. Our work will exert a profound effect in the field by substantiating a novel ?suppressed cumulative immunogenicity? framework to explain the dynamics of anti-tumor immunity in tumors with a limited number of mutated of mutated neo-antigens but high expression of retroviral chimeric antigens, which will complement the understanding that the immunoediting hypothesis has provided for carcinogen-induced tumors.

Public Health Relevance

Ovarian cancer is an immunogenic tumor that paradoxically accumulates few mutated neo-antigens. The goal of this proposal is to elucidate the role of re-activated endogenous retroviruses as potential drivers of the immunogenicity of a significant proportion of ovarian carcinomas. The proposed studies will exert a profound effect in the field, firstly, by substantiating a novel ?suppressed cumulative immunogenicity? framework to explain the dynamics of anti-tumor immunity in ovarian cancer. Besides solving a fundamental biological mystery, understanding the nature and the dynamics of ovarian cancer-specific immunogens different from mutated neo-antigens will provide a mechanistic rationale for the design of more effective interventions (e.g., vaccination or TCR cloning) specifically targeting tumor-specific antigens, 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 #
2R01CA157664-06
Application #
9171541
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2011-04-21
Project End
2021-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
6
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
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
Conejo-Garcia, Jose R; Rutkowski, Melanie R; Cubillos-Ruiz, Juan R (2016) State-of-the-art of regulatory dendritic cells in cancer. Pharmacol Ther 164:97-104
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
Clark, Curtis A; Gupta, Harshita B; Sareddy, Gangadhara et al. (2016) Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma. Cancer Res 76:6964-6974
Sheen, M R; Marotti, J D; Allegrezza, M J et al. (2016) Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer. Oncogenesis 5:e267
Allegrezza, Michael J; Rutkowski, Melanie R; Stephen, Tom L et al. (2016) IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors. Cancer Res 76:2561-72
Tesone, Amelia J; Rutkowski, Melanie R; Brencicova, Eva et al. (2016) Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells. Cell Rep 14:1774-1786
Rutkowski, Melanie R; Stephen, Tom L; Svoronos, Nikolaos et al. (2015) Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27:27-40

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