A high density of tumor-infiltrating mature dendritic cells (DC) and CD8(+) T cells correlates with a positive prognosis in a majority of human cancers. The recruitment of activated lymphocytes to the tumor microenvironment, primed to recognize tumor-associated antigens, can occur in response to immunogenic cell death (ICD) of tumor cells. ICD is characterized by the preapoptotic translocation of calreticulin (CRT) from the endoplasmic reticulum (ER) to the cell surface as a result of an ER stress response accompanied by the phosphorylation of eukaryotic initiation factor 2α (eIF2α). We conducted a retrospective study on two independent cohorts of patients with non-small cell lung cancer (NSCLC) to investigate the prognostic potential of CRT. We report that the level of CRT expression on tumor cells, which correlated with eIF2α phosphorylation, positively influenced the clinical outcome of NSCLC. High CRT expression on tumor cells was associated with a higher density of infiltrating mature DC and effector memory T-cell subsets, suggesting that CRT triggers the activation of adaptive immune responses in the tumor microenvironment. Accordingly, patients with elevated CRT expression and dense intratumoral infiltration by DC or CD8(+) T lymphocytes had the best prognosis. We conclude that CRT expression constitutes a new powerful prognostic biomarker that reflects enhanced local antitumor immune responses in the lung.

Department of Immunology Charles University 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic Sotio Prague Czech Republic

Institut National de la Santé et de la Recherche Médicale UMRS1138 Centre de Recherche des Cordeliers Paris France Université Pierre et Marie Curie Paris 6 UMRS1138 Paris France Université Paris Descartes Paris 5 UMRS1138 Paris France

Institut National de la Santé et de la Recherche Médicale UMRS1138 Centre de Recherche des Cordeliers Paris France Université Pierre et Marie Curie Paris 6 UMRS1138 Paris France Université Paris Descartes Paris 5 UMRS1138 Paris France Metabolomics and Cell Biology Platforms Gustave Roussy Villejuif France Equipe 11 labellisée Ligue contre le Cancer Centre de Recherche des Cordeliers INSERM UMRS 1138 Paris France Pôle de Biologie Hôpital Européen Georges Pompidou AP HP Paris France Karolinska Institute Department of Women's and Children's Health Karolinska University Hospital Stockholm Sweden

Institut National de la Santé et de la Recherche Médicale UMRS1138 Centre de Recherche des Cordeliers Paris France Université Pierre et Marie Curie Paris 6 UMRS1138 Paris France Université Paris Descartes Paris 5 UMRS1138 Paris France Service d'Anatomie Pathologique Hôpital Hotel Dieu AP HP Paris France

Service de Chirurgie Thoracique Hôpital Cochin AP HP Paris France

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