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Acquired immune resistance follows complete tumor regression without loss of target antigens or IFNγ signaling

Donia, Marco; Harbst, Katja LU ; van Buuren, Marit M; Kvistborg, Pia; Lindberg, Mattias F.; Andersen, Rikke Dorothea; Idorn, Manja; Ahmad, Shamaila Munir; Ellebæk, Eva and Mueller, Anja, et al. (2017) In Cancer Research 77(17). p.4562-4566
Abstract

Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I... (More)

Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8þ T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.

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published
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Cancer Research
volume
77
issue
17
pages
5 pages
publisher
American Association for Cancer Research Inc.
external identifiers
  • scopus:85028823952
  • pmid:28655789
  • wos:000409030100004
ISSN
0008-5472
DOI
10.1158/0008-5472.CAN-16-3172
language
English
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yes
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95d483b6-e0e8-401a-a0d0-bf17b6061b15
date added to LUP
2017-10-10 11:29:17
date last changed
2018-01-16 13:22:27
@article{95d483b6-e0e8-401a-a0d0-bf17b6061b15,
  abstract     = {<p>Cancer immunotherapy can result in durable tumor regressions in some patients. However, patients who initially respond often experience tumor progression. Here, we report mechanistic evidence of tumoral immune escape in an exemplary clinical case: a patient with metastatic melanoma who developed disease recurrence following an initial, unequivocal radiologic complete regression after T-cell–based immunotherapy. Functional cytotoxic T-cell responses, including responses to one mutant neoantigen, were amplified effectively with therapy and generated durable immunologic memory. However, these immune responses, including apparently effective surveillance of the tumor mutanome, did not prevent recurrence. Alterations of the MHC class I antigen-processing and presentation machinery (APM) in resistant cancer cells, but not antigen loss or impaired IFNγ signaling, led to impaired recognition by tumor-specific CD8<sup>þ</sup> T cells. Our results suggest that future immunotherapy combinations should take into account targeting cancer cells with intact and impaired MHC class I–related APM. Loss of target antigens or impaired IFNγ signaling does not appear to be mandatory for tumor relapse after a complete radiologic regression. Personalized studies to uncover mechanisms leading to disease recurrence within each individual patient are warranted.</p>},
  author       = {Donia, Marco and Harbst, Katja and van Buuren, Marit M and Kvistborg, Pia and Lindberg, Mattias F. and Andersen, Rikke Dorothea and Idorn, Manja and Ahmad, Shamaila Munir and Ellebæk, Eva and Mueller, Anja and Fagone, Paolo and Nicoletti, Ferdinando and Libra, Massimo and Lauss, Martin and Hadrup, Sine Reker and Schmidt, Henrik and Andersen, Mads Hald and Thor Straten, Per and Nilsson, Jonas and Schumacher, Ton N and Seliger, Barbara and Jönsson, Göran and Svane, Inge Marie},
  issn         = {0008-5472},
  language     = {eng},
  month        = {09},
  number       = {17},
  pages        = {4562--4566},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Acquired immune resistance follows complete tumor regression without loss of target antigens or IFNγ signaling},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-16-3172},
  volume       = {77},
  year         = {2017},
}