Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:29284.

Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal

Abhishek D. Garg _, Sanne Elsen, Dmitri V. Krysko, Peter Vandenabeele, Peter de Witte and Patrizia Agostinis

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Oncotarget. 2015; 6:26841-26860. https://doi.org/10.18632/oncotarget.4754

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Abhishek D. Garg1, Sanne Elsen2, Dmitri V. Krysko3,4, Peter Vandenabeele3,4, Peter de Witte2, Patrizia Agostinis1

1Cell Death Research & Therapy (CDRT) Unit, Department of Cellular and Molecular Medicine, KU Leuven University of Leuven, Leuven, Belgium

2Laboratory for Molecular Biodiscovery, Department of Pharmaceutical Sciences, KU Leuven, Leuven, Belgium

3Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium

4Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

Correspondence to:

Patrizia Agostinis, e-mail: patrizia.agostinis@med.kuleuven.be

Keywords: immunogenic cell death, calreticulin, patient, predictive biomarker, prognostic biomarker

Received: May 26, 2015     Accepted: July 10, 2015     Published: July 23, 2015


Immunogenic cell death (ICD) is a well-established instigator of ‘anti-cancer vaccination-effect (AVE)’. ICD has shown considerable preclinical promise, yet there remain subset of cancer patients that fail to respond to clinically-applied ICD inducers. Non-responsiveness to ICD inducers could be explained by the existence of cancer cell-autonomous, anti-AVE resistance mechanisms. However such resistance mechanisms remain poorly investigated. In this study, we have characterized for the first time, a naturally-occurring preclinical cancer model (AY27) that exhibits intrinsic anti-AVE resistance despite treatment with ICD inducers like mitoxantrone or hypericin-photodynamic therapy. Further mechanistic analysis revealed that this anti-AVE resistance was associated with a defect in exposing the important ‘eat me’ danger signal, surface-calreticulin (ecto-CRT/CALR). In an ICD setting, this defective ecto-CRT further correlated with severely reduced phagocytic clearance of AY27 cells as well as the failure of these cells to activate AVE. Defective ecto-CRT in response to ICD induction was a result of low endogenous CRT protein levels (i.e. CRTlow-phenotype) in AY27 cells. Exogenous reconstitution of ecto-rCRT (recombinant-CRT) improved the phagocytic removal of ICD inducer-treated AY27 cells, and importantly, significantly increased their AVE-activating ability. Moreover, we found that a subset of cancer patients of various cancer-types indeed possessed CALRlow or CRTlow-tumours. Remarkably, we found that tumoural CALRhigh-phenotype was predictive of positive clinical responses to therapy with ICD inducers (radiotherapy and paclitaxel) in lung and ovarian cancer patients, respectively. Furthermore, only in the ICD clinical setting, tumoural CALR levels positively correlated with the levels of various phagocytosis-associated genes relevant for phagosome maturation or processing. Thus, we reveal the existence of a cancer cell-autonomous, anti-AVE or anti-ICD resistance mechanism that has profound clinical implications for anticancer immunotherapy and cancer predictive biomarker analysis.

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