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464 Integrin αvβ1 is expressed in multiple solid tumor types and drives the adhesion of cancer associated fibroblast to latent TGF-β
  1. Vishal Kothari,
  2. Selorm Tamakloe,
  3. Colin Magowan,
  4. Gail Lee,
  5. Darren Finkelstein,
  6. Tim Hom,
  7. Manuel Munoz,
  8. Dennis Monteleone,
  9. Subramanian Karu,
  10. Erine Budi,
  11. Prerna Kotak,
  12. Shamra Martin,
  13. Katherine Jenkins,
  14. Martin Decaris,
  15. Tim Machajewski,
  16. Fernando Rock and
  17. Scott M Turner
  1. Pliant Therapeutics, South San Francisco, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background Inhibition of transforming growth factor-β (TGF-β) activity is an attractive strategy to augment the response of human tumors to immune checkpoint blockade (ICB). We previously demonstrated that dual inhibition of integrins αvβ8 and αvβ1, two cell-surface proteins that activate latent TGF-β, significantly improves the response to ICB in multiple pre-clinical tumor models. While upregulation of integrin αvβ8 in solid tumors has previously been shown to associate with poor patient outcome, expression of integrin αvβ1 in solid tumors has not previously been characterized. Here, we evaluated αvβ1 protein expression across a diverse set of human tumor tissues; and investigated the role of integrin αvβ1 in primary human cancer associated fibroblasts (CAFs).

Methods αvβ1 protein expression in human tumor tissues was evaluated via immunohistochemistry. αvβ1 protein levels in primary human CAFs (isolated from pancreatic, lung, and ovarian serous carcinoma) were quantified via custom electrochemiluminescence assay. CAF adhesion to latency associated peptide (LAP) was quantified with or without PLN-101095 (αvβ8/αvβ1 selective dual inhibitor) and PLN-78146 (αvβ1 selective inhibitor) by high-content imaging in vitro. Analysis of PLN-101095 treated human breast cancer tissues for fibrotic markers α-smooth muscle actin (αSMA) and fibroblast activating protein (FAP) was performed via immunofluorescent staining.

Results αvβ1 protein expression was confirmed by IHC in both tumor cell and CAF-rich areas of several human cancer types including breast and pancreatic tumors. When compared to normal human lung fibroblasts, the expression of αvβ1 protein was upregulated approximately 2-fold in primary human CAFs, with pancreatic CAFs showing highest upregulation (2.8-fold). Inhibition of αvβ1 with either PLN-101095 or PLN-78146 blocked the binding of CAFs to LAP, the integrin-binding region of latent TGF-β, in a significant (up to 90%, p<0.001) and dose-dependent manner, demonstrating an αvβ1-specific interaction with latent TGF-β. Furthermore, human breast tumor tissues treated with PLN-101095 ex vivo showed reduced expression of fibrotic markers αSMA (2.9-fold) and FAP (2.0-fold) compared to vehicle treated tissues, indicating a reduced TGF-β activity within the stromal regions of the tumor microenvironment.

Conclusions Here, we demonstrate that the TGF-β activating integrin αvβ1 is expressed by multiple human cancer types, is present on primary human CAFs, and mediates CAF interaction with latent TGF-β. A first-in-human clinical trial investigating the combination of PLN-101095 with ICB is currently underway.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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