# Initiation and Evolution of the Ovarian Cancer Microenvironment

> **NIH NIH R01** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $408,500

## Abstract

ABSTRACT
 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.

## Key facts

- **NIH application ID:** 9989067
- **Project number:** 5R01CA157664-11
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Jose R Conejo-Garcia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $408,500
- **Award type:** 5
- **Project period:** 2011-04-21 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989067

## Citation

> US National Institutes of Health, RePORTER application 9989067, Initiation and Evolution of the Ovarian Cancer Microenvironment (5R01CA157664-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989067. Licensed CC0.

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