Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome
Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-a...
Main Authors: | , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Taylor & Francis Group
2020-01-01
|
Series: | OncoImmunology |
Subjects: | |
Online Access: | http://dx.doi.org/10.1080/2162402X.2019.1684714 |
id |
doaj-23ce837661e44aeeb25ccff5899e605b |
---|---|
record_format |
Article |
spelling |
doaj-23ce837661e44aeeb25ccff5899e605b2021-09-24T14:41:23ZengTaylor & Francis GroupOncoImmunology2162-402X2020-01-019110.1080/2162402X.2019.16847141684714Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcomeShaokang Ma0Jonathan Chee1Vanessa S. Fear2Catherine A. Forbes3Louis Boon4Ian M. Dick5Bruce W. S. Robinson6Jenette Creaney7University of Western AustraliaUniversity of Western AustraliaUniversity of Western AustraliaUniversity of Western AustraliaBioceros B.VUniversity of Western AustraliaUniversity of Western AustraliaUniversity of Western AustraliaImmune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines.http://dx.doi.org/10.1080/2162402X.2019.1684714neo-antigencheckpoint blockadet cellsmesotheliomabiomarker |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shaokang Ma Jonathan Chee Vanessa S. Fear Catherine A. Forbes Louis Boon Ian M. Dick Bruce W. S. Robinson Jenette Creaney |
spellingShingle |
Shaokang Ma Jonathan Chee Vanessa S. Fear Catherine A. Forbes Louis Boon Ian M. Dick Bruce W. S. Robinson Jenette Creaney Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome OncoImmunology neo-antigen checkpoint blockade t cells mesothelioma biomarker |
author_facet |
Shaokang Ma Jonathan Chee Vanessa S. Fear Catherine A. Forbes Louis Boon Ian M. Dick Bruce W. S. Robinson Jenette Creaney |
author_sort |
Shaokang Ma |
title |
Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome |
title_short |
Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome |
title_full |
Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome |
title_fullStr |
Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome |
title_full_unstemmed |
Pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome |
title_sort |
pre-treatment tumor neo-antigen responses in draining lymph nodes are infrequent but predict checkpoint blockade therapy outcome |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2020-01-01 |
description |
Immune checkpoint blockade (ICPB) is a powerfully effective cancer therapy in some patients. Tumor neo-antigens are likely main targets for attack but it is not clear which and how many tumor mutations in individual cancers are actually antigenic, with or without ICPB therapy and their role as neo-antigen vaccines or as predictors of ICPB responses. To examine this, we interrogated the immune response to tumor neo-antigens in a murine model in which the tumor is induced by a natural human carcinogen (i.e. asbestos) and mimics its human counterpart (i.e. mesothelioma). We identified and screened 33 candidate neo-antigens, and found T cell responses against one candidate in tumor-bearing animals, mutant UQCRC2. Interestingly, we found a high degree of inter-animal variation in the magnitude of neo-antigen responses in otherwise identical mice. ICPB therapy with Cytotoxic T-lymphocyte-associated protein (CTLA-4) and α-glucocorticoid-induced TNFR family related gene (GITR) in doses that induced tumor regression, increased the magnitude of responses and unmasked functional T cell responses against another neo-antigen, UNC45a. Importantly, the magnitude of the pre-treatment draining lymph node (dLN) response to UNC45a closely corresponded to ICPB therapy outcomes. Surprisingly however, boosting pre-treatment UNC45a-specific T cell numbers did not improve response rates to ICPB. These observations suggest a novel biomarker approach to the clinical prediction of ICPB response and have important implications for the development of neo-antigen vaccines. |
topic |
neo-antigen checkpoint blockade t cells mesothelioma biomarker |
url |
http://dx.doi.org/10.1080/2162402X.2019.1684714 |
work_keys_str_mv |
AT shaokangma pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome AT jonathanchee pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome AT vanessasfear pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome AT catherineaforbes pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome AT louisboon pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome AT ianmdick pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome AT brucewsrobinson pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome AT jenettecreaney pretreatmenttumorneoantigenresponsesindraininglymphnodesareinfrequentbutpredictcheckpointblockadetherapyoutcome |
_version_ |
1717369726790795264 |