BACKGROUND: Adjuvanticity, which is the ability of neoplastic cells to deliver danger signals, is critical for the host immune system to mount spontaneous and therapy-driven anticancer immune responses. One of such signals, i.e., the exposure of calreticulin (CALR) on the membrane of malignant cells experiencing endoplasmic reticulum (ER) stress, is well known for its role in the activation of immune responses to dying cancer cells. However, the potential impact of CALR on the immune contexture of primary and metastatic high-grade serous carcinomas (HGSCs) and its prognostic value for patients with HGSC remains unclear. METHOD: We harnessed a retrospective cohort of primary (no = 152) and metastatic (no = 74) tumor samples from HGSC patients to investigate the CALR expression in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 302 HGSC samples was used as a confirmatory approach. RESULTS: We demonstrate that CALR exposure on the surface of primary and metastatic HGSC cells is driven by a chemotherapy-independent ER stress response and culminates with the establishment of a local immune contexture characterized by TH1 polarization and cytotoxic activity that enables superior clinical benefits. CONCLUSIONS: Our data indicate that CALR levels in primary and metastatic HGSC samples have robust prognostic value linked to the activation of clinically-relevant innate and adaptive anticancer immune responses.

Department of Dermatology Yale School of Medicine New Haven CT USA

Department of Gynecology and Obstetrics Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Gynecology and Obstetrics Charles University 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Gynecology and Obstetrics Charles University Faculty of Medicine and University Hospital Hradec Kralove Czech Republic

Department of Gynecology and Obstetrics Faculty of Medicine and University Hospital Plzen Pilsen Czech Republic

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol 5 Uvalu 84 150 00 Prague 5 Czech Republic

Department of Pathology and Molecular Medicine Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Radiation Oncology Weill Cornell Medical College New York NY USA

Inflammation Complement and Cancer INSERM U1138 Centre de Recherche des Cordeliers Paris France

Karolinska Institute Department of Women's and Children's Health Karolinska University Hospital Stockholm Sweden

Metabolomics and Cell Biology Platforms Institut Gustave Roussy Villejuif France

Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France

Sandra and Edward Meyer Cancer Center New York NY USA

Sorbonne Université Paris France

Sotio Prague Czech Republic

Suzhou Institute for Systems Biology Chinese Academy of Sciences Suzhou China

The Fingerland Department of Pathology Charles University Faculty of Medicine and University Hospital Hradec Kralove Czech Republic

Université Paris Descartes Paris France Paris France

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