The researchers tested whether Y-traps would inhibit TGFβ-induced FOXP3 expression in human T cells, in vitro — and they did.3 They next tested Y-traps’ effect on Tregs in mice bearing human tumors. Treatment of tumor-bearing mice with the CTLA4-targeted Y-trap was significantly more effective at reducing tumor-infiltrating FOXP3+ expressing Tregs compared to ipilimumab, they reported, 3 That means that Y-traps counteract FOXP3-expressing Tregs in the TGFβ-enriched tumor microenvironment.3

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The team then sought to test the in vivo antitumor efficacy of Y-traps in human tumor̶bearing mice. The CTLA4-targeted Y-trap was significantly more effective in reducing and counteracting tumor-infiltrating Tregs, activating antitumor immunity, and inhibiting tumor progression than the anti-CTLA-4 antibody ipilimumab, the team concluded.3  Likewise, their  PD-L1-targeted Y-trap that disables TGFβ, slowed the growth of tumors that did not respond to PD-L1 antibodies, avelumab, or atezolizumab, which are used in the clinic.3

“Our data demonstrate that Y-traps simultaneously disable immune checkpoints and counteract TGFβ-mediated differentiation of Tregs and immune tolerance, thereby providing a more effective immunotherapeutic strategy against cancers that fail to respond to current immune checkpoint inhibitors,” the team concluded.

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Besides their promise for treatment of advanced metastatic cancers, Dr Bedi hopes to see Y-traps applied in a neoadjuvant setting. Treatment with Y-traps could induce an antitumor immune response that reduces the risk of relapse by eliminating residual tumor cells which survive chemotherapy, radiation therapy, or surgery.

The Y-trap paradigm is extremely versatile ― in addition to addressing the immunosuppressive lynchpin of Tregs, Dr Bedi and his team have leveraged the platform to construct a family of Y-traps that address the myriad of other ways in which cancers evade the immune system and induce immune tolerance. “We have developed Y-traps that address the most pressing mechanisms of immune dysfunction in cancer, including T cell exhaustion and tumor-promoting inflammation in the tumor microenvironment,” says Dr Bedi. Y-traps that surmount these hurdles could herald a new generation of cancer immunotherapeutics that leapfrog current immune checkpoint inhibitors.


  1. Jenkins RW, Barbie DA, Flaherty KT. Mechanisms of resistance to immune checkpoint inhibitors. Br J Cancer. 2018;118:9-16. doi:10.1038/bjc.2017.434
  2. Syed V. TGF-β signaling in cancer. J Cell Biochem. 2016;117(6):1279-1287. doi:10.1002/jcb.25496
  3. Ravi R, Noonan KA, Pham V, et al. Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy. Nature Comm. 2018;9:741. doi:10.1038/s41467-017-02696-6