Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients

Fučíková, Jitka; Truxová, Iva; Hensler, Michal; Becht, Étienne; Kašíková, Lenka; Moserová, Irena; Vošáhlíková, Šárka; Kloučková, Jana; Church, S.; Cremer, Isabelle; Kepp, Oliver; Galluzzi, Lorenzo; Šálek, Cyril; Špíšek, Radek

doi:10.1182/blood-2016-08-731737

Cited by 118 publications

(103 citation statements)

References 40 publications

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“…ICD inducers like OXA, for example, could be use alongside NK cell-based therapy for maximal patient benefit [63]. Studies to improve the ICD-inducing capacity of known agents and identification of new agents are needed as well as elucidating the importance of ICD markers, like CRT, as prognostic indicators of immune cell activity [64]. Autophagy is another key factor that needs further study in the context of ICD.…”

Section: Resultsmentioning

confidence: 99%

Cytokines in immunogenic cell death: Applications for cancer immunotherapy

et al. 2017

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Despite advances in treatments like chemotherapy and radiotherapy, metastatic cancer remains a leading cause of death for cancer patients. While many chemotherapeutic agents can efficiently eliminate cancer cells, long-term protection against cancer is not achieved and many patients experience cancer recurrence. Mobilizing and stimulating the immune system against tumor cells is one of the most effective ways to protect against cancers that recur and/or metastasize. Activated tumor specific cytotoxic T lymphocytes (CTLs) can seek out and destroy metastatic tumor cells and reduce tumor lesions. Natural Killer (NK) cells are a front-line defense against drug-resistant tumors and can provide tumoricidal activity to enhance tumor immune surveillance. Cytokines like IFN-γ or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer. To this end, a group of anthracyclines or treatments like photodynamic therapy (PDT) exert their effects on cancer cells in a manner that activates the immune system. This process, known as immunogenic cell death (ICD), is characterized by the release of membrane-bound and soluble factors that boost the function of immune cells. This review will explore different types of ICD inducers, some in clinical trials, to demonstrate that optimizing the cytokine response brought about by treatments with ICD-inducing agents is central to promoting anti-cancer immunity that provides long-lasting protection against disease recurrence and metastasis.

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Section: Resultsmentioning

confidence: 99%

Cytokines in immunogenic cell death: Applications for cancer immunotherapy

et al. 2017

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“…Certain chemotherapeutic agents, in particular anthracyclines, have been shown to trigger cell death by inducing ER stress leading to a distinct phenotype of the apoptotic cells, such as surface expression of calreticulin [31]. These apoptotic cells stimulate APCs and enhance subsequent T cell responses in a process denoted ICD [32].…”

Section: Discussionmentioning

confidence: 99%

Anthracycline-based consolidation may determine outcome of post-consolidation immunotherapy in AML

Aurelius

Möllgård

Kiffin

et al. 2019

Leukemia & Lymphoma

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Consolidation chemotherapy in acute myeloid leukemia (AML) aims at eradicating residual leukemic cells and mostly comprises high-dose cytarabine with or without the addition of anthracyclines, including daunorubicin. Immunogenic cell death (ICD) may contribute to the efficacy of anthracyclines in solid cancer, but the impact of ICD in AML is only partly explored. We assessed aspects of ICD, as reflected by calreticulin expression, in primary human AML blasts and observed induction of surface calreticulin upon exposure to daunorubicin but not to cytarabine. We next assessed immune phenotypes in AML patients in complete remission (CR), following consolidation chemotherapy with or without anthracyclines. These patients subsequently received immunotherapy with histamine dihydrochloride (HDC) and IL-2. Patients who had received anthracyclines for consolidation showed enhanced frequencies of CD8 þ T EM cells in blood along with improved survival. We propose that the choice of consolidation therapy prior to AML immunotherapy may determine clinical outcome. ARTICLE HISTORY

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“…Phosphorylated eIF2α favours the translocation of ER chaperones including calreticulin (CALR) and protein disulfide-isomerase A3 (PDIA3) from the ER lumen to the cell surface 64 , where they act as 'eat-me' signals to promote phagocytosis of dying cancer cells by dendritic cells and hence initiate anticancer immunity 17 . The clinical relevance of this process is supported by the fact that CALR exposure on cancer cells correlates not only with eIF2α phosphorylation but also with prognostically favourable anticancer immune responses 65,66 . Of note, dying cancer cells can also release soluble CALR, which limits the ability of macrophages to present phagocytosed antigens (as a consequence of MHC class II downregulation) 67 and favours the accumulation of myeloidderived suppressor cells (MDSCs) 68 , hence potentially promoting tumour progression.…”

Section: Box 1 | the Dna Damage Response At A Glancementioning

confidence: 99%

Linking cellular stress responses to systemic homeostasis

Galluzzi

Yamazaki

Kroemer

2018

Nat Rev Mol Cell Biol

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401

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| Mammalian cells respond to stress by activating mechanisms that support cellular functions and hence maintain microenvironmental and organismal homeostasis. Intracellular responses to stress, their regulation and their pathophysiological implications have been extensively studied. However, little is known about the signals that emanate from stressed cells to enable a coordinated adaptive response across tissues, organs and the whole organism. Considerable evidence has now accumulated indicating that the intracellular mechanisms that are activated in response to different stresses -which include the DNA damage response, the unfolded protein response, mitochondrial stress signalling and autophagy -as well as the mechanisms ensuring the proliferative inactivation or elimination of terminally damaged cells -such as cell senescence and regulated cell death -are all coupled with the generation of signals that elicit microenvironmental and/or systemic responses. These signals, which involve changes in the surface of stressed cells and/or the secretion of soluble factors or microvesicles, generally support systemic homeostasis but can also contribute to maladaptation and disease. *

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Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients

Abstract: Key Points Malignant cells from patients with AML expose danger signals on the plasma membrane regardless of chemotherapy. Such danger signals correlate with markers of a clinically relevant tumor-specific immune response and with improved disease outcome.

Cited by 118 publications

References 40 publications

Cytokines in immunogenic cell death: Applications for cancer immunotherapy

Cytokines in immunogenic cell death: Applications for cancer immunotherapy

Anthracycline-based consolidation may determine outcome of post-consolidation immunotherapy in AML

Linking cellular stress responses to systemic homeostasis

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