Fucikova J, Truxova I, Hensler M, Becht E, Kasikova L, Moserova I, Vosahlikova S, Klouckova J, Church SE, Cremer I, Kepp O, Kroemer G, Galluzzi L, Salek C, Spisek R. Blood. 2016 Nov 1. pii: blood-2016-08-731737. [Epub ahead of print]. IF: 11.84
PharmDr. Jitka Fučíková, Ph.D., Department of Immunology
Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called ‘damage-associated molecular patterns’, DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death (ICD) to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from acute myeloid leukemia (AML) patients exposed multiple DAMPs including calreticulin (CRT), heat-shock protein 70 (HSP70) and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed (ecto-)CRT correlated with an increased proportion of natural killer (NK) cells and effector memory CD4+ and CD8+ T cells in the periphery. Moreover, CRT exposure on the plasma membrane of malignant blasts positively correlated with the frequency of circulating T cells specific for leukemia-associated antigens (LAAs), indicating that ecto-CRT favors the initiation of anticancer immunity in AML patients. Finally, while the levels of ecto-HSP70, ecto-HSP90 and ecto-CRT were all associated with improved relapse-free survival, only CRT exposure significantly correlated with superior overall survival. Thus, CRT exposure represents a novel powerful prognostic biomarker for AML patients, reflecting the activation of a clinically relevant AML-specific immune response.
For this topic, see also following article:
Calreticulin Expression in Human Non-Small Cell Lung Cancers Correlates with Increased Accumulation of Antitumor Immune Cells and Favorable Prognosis.
Fucikova J, Becht E, Iribarren K, Goc J, Remark R, Damotte D, Alifano M, Devi P, Biton J, Germain C, Lupo A, Fridman WH, Dieu-Nosjean MC, Kroemer G, Sautès-Fridman C, Cremer I. Cancer Research. 2016 Apr 1;76(7):1746–56. doi: 10.1158/0008-5472.CAN-15-1142. Epub 2016 Feb 3. IF: 8.556
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.