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.
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.
|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|
|Karakashev, Sergey; Zhu, Hengrui; Wu, Shuai et al. (2018) CARM1-expressing ovarian cancer depends on the histone methyltransferase EZH2 activity. Nat Commun 9:631|
|Fukumoto, Takeshi; Park, Pyoung Hwa; Wu, Shuai et al. (2018) Repurposing Pan-HDAC Inhibitors for ARID1A-Mutated Ovarian Cancer. Cell Rep 22:3393-3400|
|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|
|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|
|Allegrezza, Michael J; Conejo-Garcia, Jose R (2017) Targeted Therapy and Immunosuppression in the Tumor Microenvironment. Trends Cancer 3:19-27|
|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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