Abstract | BACKGROUND: METHODS: To understand the distinct mechanism of AB680 in comparison to that of a neutralizing antibody against murine PD-1 used as a PD-1 blocker, we performed single-cell RNA sequencing of CD45+ tumor-infiltrating lymphocytes from untreated controls (n=3) and from AB680-treated (n=3) and PD-1-blockade-treated murine CRC in vivo models. We also used flow cytometry, Azoxymethane (AOM)/ Dextran Sulfate Sodium (DSS) models, and in vitro functional assays to validate our new findings. RESULTS: We initially observed that the expressions of Nt5e (a gene for CD73) and Entpd1 (a gene for CD39) affect T cell receptor (TCR) diversity and transcriptional profiles of T cells, thus suggesting their critical roles in T cell exhaustion within tumor. Importantly, PD-1 blockade significantly increased the TCR diversity of Entpd1-negative T cells and Pdcd1-positive T cells. Additionally, we determined that AB680 improved the anticancer functions of immunosuppressed cells such as Treg and exhausted T cells, while the PD-1 blocker quantitatively reduced Malat1high Treg and M2 macrophages. We also verified that PD-1 blockade induced Treg depletion in AOM/DSS CRC in vivo models, and we confirmed that AB680 treatment caused increased activation of CD8+ T cells using an in vitro T cell assay. CONCLUSIONS: The intratumoral immunomodulation of CD73 inhibition is distinct from PD-1 inhibition and exhibits potential as a novel anticancer immunotherapy for CRC, possibly through a synergistic effect when combined with PD-1 blocker treatments. This study may contribute to the ongoing development of anticancer immunotherapies targeting refractory CRC.
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Authors | Miok Kim, Yong Ki Min, Jinho Jang, Hyejin Park, Semin Lee, Chang Hoon Lee |
Journal | Journal for immunotherapy of cancer
(J Immunother Cancer)
Vol. 9
Issue 7
(07 2021)
ISSN: 2051-1426 [Electronic] England |
PMID | 34253638
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
Chemical References |
- Programmed Cell Death 1 Receptor
- 5'-Nucleotidase
|
Topics |
- 5'-Nucleotidase
(metabolism)
- Animals
- Colorectal Neoplasms
(drug therapy, genetics)
- Humans
- Immunotherapy
(methods)
- Male
- Mice
- Programmed Cell Death 1 Receptor
(metabolism)
- Sequence Analysis, RNA
(methods)
- Single-Cell Analysis
(methods)
- Tumor Microenvironment
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