CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells
Strategies to boost anti-tumor immunity are urgently needed to treat therapy-resistant late-stage cancers, including colorectal cancers (CRCs). Cytokine stimulation and genetic modifications with chimeric antigen receptors (CAR) represent promising strategies to more specifically redirect anti-tumor...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.883694/full |
| _version_ | 1818240269699514368 |
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| author | Ali Bashiri Dezfouli Mina Yazdi Mohamed-Reda Benmebarek Melissa Schwab Stefanos Michaelides Arianna Miccichè Dirk Geerts Stefan Stangl Stefan Stangl Sarah Klapproth Ernst Wagner Sebastian Kobold Sebastian Kobold Gabriele Multhoff |
| author_facet | Ali Bashiri Dezfouli Mina Yazdi Mohamed-Reda Benmebarek Melissa Schwab Stefanos Michaelides Arianna Miccichè Dirk Geerts Stefan Stangl Stefan Stangl Sarah Klapproth Ernst Wagner Sebastian Kobold Sebastian Kobold Gabriele Multhoff |
| author_sort | Ali Bashiri Dezfouli |
| collection | DOAJ |
| description | Strategies to boost anti-tumor immunity are urgently needed to treat therapy-resistant late-stage cancers, including colorectal cancers (CRCs). Cytokine stimulation and genetic modifications with chimeric antigen receptors (CAR) represent promising strategies to more specifically redirect anti-tumor activities of effector cells like natural killer (NK) and T cells. However, these approaches are critically dependent on tumor-specific antigens while circumventing the suppressive power of the solid tumor microenvironment and avoiding off-tumor toxicities. Previously, we have shown that the stress-inducible heat shock protein 70 (Hsp70) is frequently and specifically expressed on the cell surface of many different, highly aggressive tumors but not normal tissues. We could take advantage of tumors expressing Hsp70 on their membrane (‘mHsp70’) to attract and engage NK cells after in vitro stimulation with the 14-mer Hsp70 peptide TKDNNLLGRFELSG (TKD) plus low dose interleukin (IL)-2. However, a potential limitation of activated primary NK cells after adoptive transfer is their comparably short life span. T cells are typically long-lived but do not recognize mHsp70 on tumor cells, even after stimulation with TKD/IL-2. To combine the advantages of mHsp70-specificity with longevity, we constructed a CAR having specificity for mHsp70 and retrovirally transduced it into primary T cells. Co-culture of anti-Hsp70 CAR-transduced T cells with mHsp70-positive tumor cells stimulates their functional responsiveness. Herein, we demonstrated that human CRCs with a high mHsp70 expression similarly attract TKD/IL-2 stimulated NK cells and anti-Hsp70 CAR T cells, triggering the release of their lytic effector protein granzyme B (GrB) and the pro-inflammatory cytokine interferon (IFN)-γ, after 4 and 24 hours, respectively. In sum, stimulated NK cells and anti-Hsp70 CAR T cells demonstrated comparable anti-tumor effects, albeit with somewhat differing kinetics. These findings, together with the fact that mHsp70 is expressed on a large variety of different cancer entities, highlight the potential of TKD/IL-2 pre-stimulated NK, as well as anti-Hsp70 CAR T cells to provide a promising direction in the field of targeted, cell-based immunotherapies which can address significant unmet clinical needs in a wide range of cancer settings. |
| first_indexed | 2024-12-12T13:10:46Z |
| format | Article |
| id | doaj.art-75a3273165cd42b887f3eec94bcb757f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T13:10:46Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-75a3273165cd42b887f3eec94bcb757f2022-12-22T00:23:32ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.883694883694CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK CellsAli Bashiri Dezfouli0Mina Yazdi1Mohamed-Reda Benmebarek2Melissa Schwab3Stefanos Michaelides4Arianna Miccichè5Dirk Geerts6Stefan Stangl7Stefan Stangl8Sarah Klapproth9Ernst Wagner10Sebastian Kobold11Sebastian Kobold12Gabriele Multhoff13Central Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität (LMU), Munich, GermanyCenter of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research Deutsches Zentrum für Lungenforschung (DZL), Munich, GermanyCentral Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, GermanyCenter of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research Deutsches Zentrum für Lungenforschung (DZL), Munich, GermanyGlycostem Therapeutics BV, Oss, NetherlandsGlycostem Therapeutics BV, Oss, NetherlandsCentral Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, GermanyDepartment of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, GermanyInstitute of Experimental Hematology, Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, GermanyPharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität (LMU), Munich, GermanyCenter of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research Deutsches Zentrum für Lungenforschung (DZL), Munich, GermanyGerman Center for Translational Cancer Research Deutsches Konsortium für Translationale Krebsforschung (DKTK), Partner Site Munich, Munich, GermanyCentral Institute for Translational Cancer Research Technische Universität München (TranslaTUM), Department of Radiation Oncology, Klinikum rechts der Isar, Munich, GermanyStrategies to boost anti-tumor immunity are urgently needed to treat therapy-resistant late-stage cancers, including colorectal cancers (CRCs). Cytokine stimulation and genetic modifications with chimeric antigen receptors (CAR) represent promising strategies to more specifically redirect anti-tumor activities of effector cells like natural killer (NK) and T cells. However, these approaches are critically dependent on tumor-specific antigens while circumventing the suppressive power of the solid tumor microenvironment and avoiding off-tumor toxicities. Previously, we have shown that the stress-inducible heat shock protein 70 (Hsp70) is frequently and specifically expressed on the cell surface of many different, highly aggressive tumors but not normal tissues. We could take advantage of tumors expressing Hsp70 on their membrane (‘mHsp70’) to attract and engage NK cells after in vitro stimulation with the 14-mer Hsp70 peptide TKDNNLLGRFELSG (TKD) plus low dose interleukin (IL)-2. However, a potential limitation of activated primary NK cells after adoptive transfer is their comparably short life span. T cells are typically long-lived but do not recognize mHsp70 on tumor cells, even after stimulation with TKD/IL-2. To combine the advantages of mHsp70-specificity with longevity, we constructed a CAR having specificity for mHsp70 and retrovirally transduced it into primary T cells. Co-culture of anti-Hsp70 CAR-transduced T cells with mHsp70-positive tumor cells stimulates their functional responsiveness. Herein, we demonstrated that human CRCs with a high mHsp70 expression similarly attract TKD/IL-2 stimulated NK cells and anti-Hsp70 CAR T cells, triggering the release of their lytic effector protein granzyme B (GrB) and the pro-inflammatory cytokine interferon (IFN)-γ, after 4 and 24 hours, respectively. In sum, stimulated NK cells and anti-Hsp70 CAR T cells demonstrated comparable anti-tumor effects, albeit with somewhat differing kinetics. These findings, together with the fact that mHsp70 is expressed on a large variety of different cancer entities, highlight the potential of TKD/IL-2 pre-stimulated NK, as well as anti-Hsp70 CAR T cells to provide a promising direction in the field of targeted, cell-based immunotherapies which can address significant unmet clinical needs in a wide range of cancer settings.https://www.frontiersin.org/articles/10.3389/fimmu.2022.883694/fulladoptive ImmunotherapyHsp70IL-2anti-Hsp70 CAR T cellsactivated NK cells |
| spellingShingle | Ali Bashiri Dezfouli Mina Yazdi Mohamed-Reda Benmebarek Melissa Schwab Stefanos Michaelides Arianna Miccichè Dirk Geerts Stefan Stangl Stefan Stangl Sarah Klapproth Ernst Wagner Sebastian Kobold Sebastian Kobold Gabriele Multhoff CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells Frontiers in Immunology adoptive Immunotherapy Hsp70 IL-2 anti-Hsp70 CAR T cells activated NK cells |
| title | CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells |
| title_full | CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells |
| title_fullStr | CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells |
| title_full_unstemmed | CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells |
| title_short | CAR T Cells Targeting Membrane-Bound Hsp70 on Tumor Cells Mimic Hsp70-Primed NK Cells |
| title_sort | car t cells targeting membrane bound hsp70 on tumor cells mimic hsp70 primed nk cells |
| topic | adoptive Immunotherapy Hsp70 IL-2 anti-Hsp70 CAR T cells activated NK cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.883694/full |
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