Isoform specific anti-TGFβ therapy enhances antitumor efficacy in mouse models of cancer
© 2021. The Author(s)..
TGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGFβ1 and TGFβ3. Depending on local expression of TGFβ isoforms, isoform specific inhibition of either TGFβ1 or TGFβ3 may be effective. The TGFβ signature of CT26 colon carcinoma is defined by TGFβ1 and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8+ T cell function. To overcome the local immunosuppressive environment, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:4 |
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| Enthalten in: |
Communications biology - 4(2021), 1 vom: 17. Nov., Seite 1296 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gupta, Aditi [VerfasserIn] |
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| Links: |
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| Themen: |
Antineoplastic Agents |
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| Anmerkungen: |
Date Completed 20.12.2021 Date Revised 23.04.2022 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s42003-021-02773-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM333274814 |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021. The Author(s). | ||
| 520 | |a TGFβ is a potential target in cancer treatment due to its dual role in tumorigenesis and homeostasis. However, the expression of TGFβ and its inhibition within the tumor microenvironment has mainly been investigated in stroma-heavy tumors. Using B16 mouse melanoma and CT26 colon carcinoma as models of stroma-poor tumors, we demonstrate that myeloid/dendritic cells are the main sources of TGFβ1 and TGFβ3. Depending on local expression of TGFβ isoforms, isoform specific inhibition of either TGFβ1 or TGFβ3 may be effective. The TGFβ signature of CT26 colon carcinoma is defined by TGFβ1 and TGFβ1 inhibition results in tumor delay; B16 melanoma has equal expression of both isoforms and inhibition of either TGFβ1 or TGFβ3 controls tumor growth. Using T cell functional assays, we show that the mechanism of tumor delay is through and dependent on enhanced CD8+ T cell function. To overcome the local immunosuppressive environment, we found that combining TGFβ inhibition with immune checkpoint blockade results in improved tumor control. Our data suggest that TGFβ inhibition in stroma poor tumors shifts the local immune environment to favor tumor suppression | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Transforming Growth Factor beta |2 NLM | |
| 700 | 1 | |a Budhu, Sadna |e verfasserin |4 aut | |
| 700 | 1 | |a Fitzgerald, Kelly |e verfasserin |4 aut | |
| 700 | 1 | |a Giese, Rachel |e verfasserin |4 aut | |
| 700 | 1 | |a Michel, Adam O |e verfasserin |4 aut | |
| 700 | 1 | |a Holland, Aliya |e verfasserin |4 aut | |
| 700 | 1 | |a Campesato, Luis Felipe |e verfasserin |4 aut | |
| 700 | 1 | |a van Snick, Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Uyttenhove, Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Ritter, Gerd |e verfasserin |4 aut | |
| 700 | 1 | |a Wolchok, Jedd D |e verfasserin |4 aut | |
| 700 | 1 | |a Merghoub, Taha |e verfasserin |4 aut | |
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