BACKGROUND:Serous tubal intraepithelial carcinoma (STIC) and the p53 signature in tubal mucosa have been supported to be precursor lesions in high-grade serous carcinoma (HGSC) of the fallopian tube, ovary, and peritoneum. It remains critical to find biomarkers for precursor lesions in order to detect HGSCs efficiently. IMP3 is an oncoprotein that has been explored in human malignancies. No studies have specifically addressed the expression of IMP3 in precursor or early lesions of HGSC. The main purposes of this study are to evaluate if IMP3 plays any role in the process of pelvic serous carcinogenesis by examining its expression in HGSC precursor lesions, to examine the relationship between IMP3 and p53 in those precursor lesions, and to check if IMP3 can be used as a biomarker for early diagnosis.METHODS:Immunohistochemistry for IMP3 and p53 was performed and evaluated in 48 HGSCs with STIC, 62 HGSCs without STIC, and 60 benign cases as negative controls. Sections of fallopian tubes with or without STIC , as well as cancers within the ovaries, were studied. IMP3 signature was defined as strong IMP3 cytoplasmic staining in 10 or more consecutive benign-looking tubal epithelial cells. The relationship between IMP3 and p53 overexpression was examined.RESULTS:In the 48 HGSC patients with STIC, IMP3 was positive in 46% of STIC lesions and had a similar positive rate in the invasive components of HGSC. IMP3 was also expressed in normal appearing tubal epithelia (IMP3 signature) in 15 (31%) of 48 HGSC cases with STIC and 10 (16%) of 62 cases without STIC. In contrast, no single IMP3 signature was found in the benign control group. Concordant expression of IMP3 and p53 signatures in the STIC group was found in up to one-third of the cases. There were also five (10%) STIC cases with positive IMP3 and negative p53.CONCLUSIONS:We conclude that IMP3 may be involved in the process and progression of pelvic HGSC and may serve as a complimentary biomarker in diagnosing STIC.

Background: Mounting evidence suggests the fallopian tube as the origin for ovarian high grade serous carcinoma (HGSC). We attempted to identify the tubal cytological features that allow us to distinguish malignant from benign conditions. Methods: Tubal specimens (n = 56) were collected from patients who underwent bilateral salpingo-oophorectomy (BSO) due to various clinical indications. A standard procedure to collect fallopian tube brushings from freshly received surgical specimens was developed. Cytological diagnoses were classified into three categories: benign, atypical, and suspicious for malignancy/malignant. Cytological variables of individual cells and epithelia were subjected to statistical analysis. The fallopian tube histology was used as diagnostic reference for confirmation of cytology diagnosis. Results: Among the 56 fallopian tube specimens, 2 (3.7 %) showed inadequate cellularity preventing further evaluation, 11 (20.4 %) were diagnosed as malignant or suspicious of malignancy, 7 were atypical, and 36 were benign. The presence of three dimensional clusters (p < 0.0001, Fisher's Exact Test), or prominent nucleoli (p = 0.0252, Fisher Exact test) was highly correlated with the diagnosis of malignancy. The suspicious malignant/malignant cytological diagnosis was also highly correlated with presence of HGSC with or without serous tubal intraepithelial carcinoma (STIC). Conclusions: Tubal cytology may be useful for ovarian cancer screening and early detection.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and urgently requires new therapies. Oncolytic viruses (OV) are a strong contender. OVs interact with immune components of the TME, which can be altered due to specific genetic mutations. The present study evaluates the impact of specific tumour mutations on the response to carboplatin, the current standard of care, and VSV∆M51, a promising OV candidate. After a study of genetically diverse models, constitutive KRas activation enhanced VSV∆M51 replication in-vitro and sensitivity in syngeneic in-vivo models. VSV∆M51 prolonged survival in syngeneic tumour- bearing mice with KRas, Trp53 and Pten mutations, including one tumour model that did not respond to carboplatin. Response to VSV∆M51 in-vivo was associated with activation of CD4+ and CD8+ T lymphocytes in the peritoneal TME. In summary, VSV∆M51-based immunotherapy has shown promise in diverse murine models of EOC bearing clinically relevant mutations.

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Le carcinome séreux de haut grade (CSHG) est le sous-type histologique le plus courant du cancer de l'ovaire et demeure le cancer le plus meurtrier de l'appareil reproducteur féminin. Les récents progrès de l'immunothérapie contre le cancer ont mis en évidence un énorme potentiel thérapeutique pour les patientes confrontées à des besoins non satisfaits de soins de santé pour le traitement des CSHG. Une étape cruciale pour le développement de nouvelles stratégies thérapeutiques consiste à identifier les antigènes spécifiques des tumeurs (TSA), c’est-à-dire des antigènes majeurs d'histocompatibilité de classe I présents à la surface des cellules cancéreuses mais absents des cellules normales. Ces TSA peuvent être reconnus par les cellules T et sont des éléments essentiels dans la conception de vaccins destinés à stimuler les réponses immunitaires anticancéreuses. Les travaux menés dans le cadre de mon programme de doctorat ont porté sur l'identification et la caractérisation des TSAs dans les CSHG. Les premières études sur les TSAs ont été dirigées uniquement vers l’identification de TSAs dérivés de mutations dans les régions codantes, menant à l’identification d’antigènes très rares et privés dans les CSHG. Dans notre première étude, nous avons analysé 23 échantillons de cancer de l'ovaire en utilisant une approche protéogénomique nous permettant d'étudier à la fois les régions génomiques codantes et non codantes. Ce faisant, nous avons identifié un total de 103 TSAs, dont 91 qui ne portaient pas de mutations et dérivaient de séquences présumées non-codantes. Nous appelons ces antigènes « TSAs exprimés de manière aberrante (aeTSAs) » puisqu’ils sont exprimés de manière aberrante dans les échantillons de cancer mais absents dans les tissus normaux. Contrairement aux TSAs mutés, qui sont davantage patient- spécifiques, l’ARN codant pour les aeTSAs est exprimé par plusieurs patientes atteints d’un CSHG, celles-ci exprimant individuellement une médiane de 5 aeTSAs. De par leur nombre élevé et du fait que leur expression soit partagée dans une large population de patientes atteints de CSHG, les aeTSAs représentent des cibles intéressantes pour l'immunothérapie du cancer. En raison de leur origine principalement non codante, la nature et la régulation des aeTSAs sont peu connues. Notre seconde étude a donc porté sur la régulation de la biogenèse des aeTSAs. L’analyse de données de séquençage de l'ARN de CSHG en cellule unique a montré une expression enrichie et spécifique des gènes sources des aeTSAs dans les cellules cancéreuses. Grâce à une analyse transcriptomique plus poussée, nous avons identifié de nouveaux transcrits récurrents codant pour les aeTSAs et avons déterminé que ces transcrits sont largement surexprimés dans les CSHG. De plus, nous avons déterminé que les aeTSAs issus d'événements de traduction non canonique sont codés préférentiellement par des cadres de lecture ouverts courts et générés à partir de régions près de l'extrémité C-terminale. Finalement, nos analyses sur l'accessibilité de la chromatine et les modifications des histones supportent l’hypothèse que les transcrits codant pour les aeTSAs ont recourt à des promoteurs alternatifs, ce qui suggère un rôle important de l'épigénome du cancer dans la genèse du paysage antigénique. Nos travaux représentent la première analyse complète des antigènes provenant des régions codantes et non codantes dans les tumeurs ovariennes. Nous avons pu dresser une liste exhaustive de cibles thérapeutiques potentielles et mieux comprendre leur biogenèse. Nos travaux portant sur la découverte et la caractérisation des aeTSAs favoriseront la conception de nouvelles immunothérapies ciblant ces antigènes et ce qui sera bénéfique pour un plus grand nombre de patientes atteintes de CSHG. / High-grade serous carcinoma (HGSC) is the most common histologic subtype of ovarian cancer and the most lethal cancer in the female reproductive system. Recent advances in cancer immunotherapy have highlighted enormous therapeutical potential for patients facing unmet clinical needs in HGSC treatment. A crucial step for developing new therapeutic strategies is identifying targetable tumor-specific antigens (TSAs), namely the major histocompatibility class I antigens presented on the cancer cell surface but absent from normal cells. These TSAs can be recognized by T cells and are essential elements in designing vaccines to stimulate anti-cancer immune responses. The goal of my Ph.D. thesis was to identify and characterize TSAs in HGSC. In early studies of TSAs, most groups focused solely on TSAs derived from mutations in coding regions, which reported very rare and private antigens in HGSCs. In our first study, we used a proteogenomic workflow that enabled us to survey both coding and noncoding sequences to analyse 23 ovarian cancer samples. We uncovered 103 TSAs, 91 of which were not mutated and derived mainly from allegedly noncoding sequences. We call these antigens aberrantly expressed TSAs (aeTSAs), for their lack of expression in normal tissues while being aberrantly expressed in cancer samples. Unlike the mutated TSAs unique to individual tumors, the aeTSAs have shared RNA expression in HGSC tumors, with an estimated median presentation of five per patient. Because of their number and shared expression in a large population, we consider aeTSAs attractive targets for immunotherapy. Due to their primarily noncoding origin, little is known about the nature and regulation of aeTSAs. In our second study, we explored the biogenesis of the aeTSAs. HGSC single-cell RNA sequencing data showed a malignant cell-specific/enriched expression of aeTSA source genes. Further transcriptomic profiling identified novel recurrent transcripts coding for aeTSAs and revealed broad overexpression of aeTSA-coding transcripts in HGSC. Moreover, we showed that aeTSAs derived from noncanonical translation events are coded preferably by short open reading frames and generated from regions close to the C-terminus. Our analysis of chromatin accessibility and histone modifications support a differential promoter activity for aeTSA-coding transcripts, suggesting an important role of cancer epigenome in shaping the antigen landscape. Our work is the first comprehensive analysis of ovarian tumor antigens derived from both coding and noncoding regions. We reported an extensive list of potential therapeutic targets and provided insights into their biogenesis. Our work on discovering and characterizing shared TSAs shall promote the design of new antigen-targeting immunotherapy that benefits more HGSC patients.