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

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 exp...

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Main Authors:	Garg, Abhishek D., Elsen, Sanne, Krysko, Dmitri V., Vandenabeele, Peter, de Witte, Peter, Agostinis, Patrizia
Format:	Online
Language:	English
Published:	Impact Journals LLC 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694957/

id	pubmed-4694957
recordtype	oai_dc
spelling	pubmed-46949572016-01-20 Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal Garg, Abhishek D. Elsen, Sanne Krysko, Dmitri V. Vandenabeele, Peter de Witte, Peter Agostinis, Patrizia Research Paper 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. Impact Journals LLC 2015-07-23 /pmc/articles/PMC4694957/ /pubmed/26314964 Text en Copyright: © 2015 Garg et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Garg, Abhishek D. Elsen, Sanne Krysko, Dmitri V. Vandenabeele, Peter de Witte, Peter Agostinis, Patrizia
spellingShingle	Garg, Abhishek D. Elsen, Sanne Krysko, Dmitri V. Vandenabeele, Peter de Witte, Peter Agostinis, Patrizia Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal
author_facet	Garg, Abhishek D. Elsen, Sanne Krysko, Dmitri V. Vandenabeele, Peter de Witte, Peter Agostinis, Patrizia
author_sort	Garg, Abhishek D.
title	Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal
title_short	Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal
title_full	Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal
title_fullStr	Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal
title_full_unstemmed	Resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal
title_sort	resistance to anticancer vaccination effect is controlled by a cancer cell-autonomous phenotype that disrupts immunogenic phagocytic removal
description	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.
publisher	Impact Journals LLC
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694957/
_version_	1613517847909105664

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

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