ORCID Profile
0000-0002-4731-4969
Current Organisations
IT University of Copenhagen
,
Københavns Universitet
,
Center for Cancer Immune Therapy
,
Open University
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Publications
More tricks with tetramers: a practical guide to staining T cells with peptide–MHC multimers
Publisher: Wiley
Date: 04-08-2015
DOI: 10.1111/IMM.12499
Antibody Stabilization of Peptide–MHC Multimers Reveals Functional T Cells Bearing Extremely Low-Affinity TCRs
Publisher: The American Association of Immunologists
Date: 12-11-2015
Abstract: Fluorochrome-conjugated peptide–MHC (pMHC) multimers are commonly used in combination with flow cytometry for direct ex vivo visualization and characterization of Ag-specific T cells, but these reagents can fail to stain cells when TCR affinity and/or TCR cell-surface density are low. pMHC multimer staining of tumor-specific, autoimmune, or MHC class II–restricted T cells can be particularly challenging, as these T cells tend to express relatively low-affinity TCRs. In this study, we attempted to improve staining using anti-fluorochrome unconjugated primary Abs followed by secondary staining with anti-Ab fluorochrome-conjugated Abs to lify fluorescence intensity. Unexpectedly, we found that the simple addition of an anti-fluorochrome unconjugated Ab during staining resulted in considerably improved fluorescence intensity with both pMHC tetramers and dextramers and with PE-, allophycocyanin-, or FITC-based reagents. Importantly, when combined with protein kinase inhibitor treatment, Ab stabilization allowed pMHC tetramer staining of T cells even when the cognate TCR–pMHC affinity was extremely low (KD & mM) and produced the best results that we have observed to date. We find that this inexpensive addition to pMHC multimer staining protocols also allows improved recovery of cells that have recently been exposed to Ag, improvements in the recovery of self-specific T cells from PBMCs or whole-blood s les, and the use of less reagent during staining. In summary, Ab stabilization of pMHC multimers during T cell staining extends the range of TCR affinities that can be detected, yields considerably enhanced staining intensities, and is compatible with using reduced amounts of these expensive reagents.
Acquired Immune Resistance Follows Complete Tumor Regression without Loss of Target Antigens or IFNγ Signaling
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/0008-5472.CAN-16-3172
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 lified 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+ 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 in idual patient are warranted. Cancer Res 77(17) 4562–6. ©2017 AACR.
Future perspectives in melanoma research “Melanoma Bridge”, Napoli, November 30th–3rd December 2016
Publisher: Springer Science and Business Media LLC
Date: 16-11-2017
Immunotherapy Bridge 2016 and Melanoma Bridge 2016: meeting abstracts
Publisher: Springer Science and Business Media LLC
Date: 2017
Related Organisations
Open University
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Per thor Straten.