Efficacy and pharmacodynamic effect of anti-CD73 and anti-PD-L1 monoclonal antibodies in combination with cytotoxic therapy : observations from mouse tumor models
CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
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| Enthalten in: |
Cancer biology & therapy - 25(2024), 1 vom: 31. März, Seite 2296048 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kaistha, Brajesh P [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.01.2024 Date Revised 11.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1080/15384047.2023.2296048 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366971581 |
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| 100 | 1 | |a Kaistha, Brajesh P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Efficacy and pharmacodynamic effect of anti-CD73 and anti-PD-L1 monoclonal antibodies in combination with cytotoxic therapy |b observations from mouse tumor models |
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| 500 | |a Date Revised 11.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a CD73 is a cell surface 5'nucleotidase (NT5E) and key node in the catabolic process generating immunosuppressive adenosine in cancer. Using a murine monoclonal antibody surrogate of Oleclumab, we investigated the effect of CD73 inhibition in concert with cytotoxic therapies (chemotherapies as well as fractionated radiotherapy) and PD-L1 blockade. Our results highlight improved survival in syngeneic tumor models of colorectal cancer (CT26 and MC38) and sarcoma (MCA205). This therapeutic outcome was in part driven by cytotoxic CD8 T-cells, as evidenced by the detrimental effect of CD8 depleting antibody treatment of MCA205 tumor bearing mice treated with anti-CD73, anti-PD-L1 and 5-Fluorouracil+Oxaliplatin (5FU+OHP). We hypothesize that the improved responses are tumor microenvironment (TME)-driven, as suggested by the lack of anti-CD73 enhanced cytopathic effects mediated by 5FU+OHP on cell lines in vitro. Pharmacodynamic analysis, using imaging mass cytometry and RNA-sequencing, revealed noteworthy changes in specific cell populations like cytotoxic T cells, B cells and NK cells in the CT26 TME. Transcriptomic analysis highlighted treatment-related modulation of gene profiles associated with an immune response, NK and T-cell activation, T cell receptor signaling and interferon (types 1 & 2) pathways. Inclusion of comparator groups representing the various components of the combination allowed deconvolution of contribution of the individual therapeutic elements; highlighting specific effects mediated by the anti-CD73 antibody with respect to immune-cell representation, chemotaxis and myeloid biology. These pre-clinical data reflect complementarity of adenosine blockade with cytotoxic therapy, and T-cell checkpoint inhibition, and provides new mechanistic insights in support of combination therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anti-CD73 | |
| 650 | 4 | |a Oleclumab | |
| 650 | 4 | |a adenosine | |
| 650 | 4 | |a bulk RNA-sequencing (RNAseq) | |
| 650 | 4 | |a chemotherapy | |
| 650 | 4 | |a immune-checkpoint blockade (ICB) | |
| 650 | 4 | |a immunotherapy | |
| 650 | 4 | |a radiotherapy | |
| 650 | 4 | |a syngeneic tumor models | |
| 650 | 4 | |a tumor microenvironment (TME) | |
| 650 | 7 | |a Antibodies, Monoclonal |2 NLM | |
| 650 | 7 | |a Immunosuppressive Agents |2 NLM | |
| 650 | 7 | |a Adenosine |2 NLM | |
| 650 | 7 | |a K72T3FS567 |2 NLM | |
| 650 | 7 | |a Fluorouracil |2 NLM | |
| 650 | 7 | |a U3P01618RT |2 NLM | |
| 700 | 1 | |a Kar, Gozde |e verfasserin |4 aut | |
| 700 | 1 | |a Dannhorn, Andreas |e verfasserin |4 aut | |
| 700 | 1 | |a Watkins, Amanda |e verfasserin |4 aut | |
| 700 | 1 | |a Opoku-Ansah, Grace |e verfasserin |4 aut | |
| 700 | 1 | |a Ilieva, Kristina |e verfasserin |4 aut | |
| 700 | 1 | |a Mullins, Stefanie |e verfasserin |4 aut | |
| 700 | 1 | |a Anderton, Judith |e verfasserin |4 aut | |
| 700 | 1 | |a Galvani, Elena |e verfasserin |4 aut | |
| 700 | 1 | |a Garcon, Fabien |e verfasserin |4 aut | |
| 700 | 1 | |a Lapointe, Jean-Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Lee |e verfasserin |4 aut | |
| 700 | 1 | |a Hair, James |e verfasserin |4 aut | |
| 700 | 1 | |a Slidel, Tim |e verfasserin |4 aut | |
| 700 | 1 | |a Luheshi, Nadia |e verfasserin |4 aut | |
| 700 | 1 | |a Ryan, Kelli |e verfasserin |4 aut | |
| 700 | 1 | |a Hardaker, Elizabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Dovedi, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Kumar, Rakesh |e verfasserin |4 aut | |
| 700 | 1 | |a Wilkinson, Robert W |e verfasserin |4 aut | |
| 700 | 1 | |a Hammond, Scott A |e verfasserin |4 aut | |
| 700 | 1 | |a Eyles, Jim |e verfasserin |4 aut | |
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