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447 VISTA targeting remodels the tumor microenvironment to overcome adaptive resistance
  1. Janet Lines1,
  2. Evelien Schaafsma1,
  3. Walburga Croteau1,
  4. Mohamed ElTanbouly1,
  5. Elizabeth Nowak1,
  6. Nicole Smits1,
  7. Cecilia Webber1,
  8. Dina Rabadi1,
  9. Jie Deng2,
  10. Chao Cheng3 and
  11. Randolph Noelle1
  1. 1Dartmouth College, Lebanon, NH, USA
  2. 2UCLA, Los Angeles, CA, USA
  3. 3Baylor College of Medicine, Houston, TX, USA


Background VISTA is a negative checkpoint regulator prominently expressed in the TME of a wide variety of cancers. In a preclinical model of colorectal cancer, monotherapy of small tumors (40 mm3) with anti-VISTA results in markedly slowed tumor growth. Mice bearing significantly larger tumors (600 mm3) are resistant to anti-PD-1 and anti-CTLA4 treatment and all mice die following treatment, indicating checkpoint resistance. Inclusion of anti-VISTA leads to complete rejection of 50% of tumors.

Methods The underlying therapeutic mechanisms of leading to enhanced anti-tumor immunity in both models was investigated by high-dimensional scRNAseq of the CD45+ immune infiltrate of tumors 10 days after treatment initiation.

Results In both modes, anti-VISTA treatment stimulated several pathways involving myeloid activation and antigen-presentation. Multi-spectral imaging of anti-VISTA treated tumors supported increased antigen presentation, and suppression assays showed that the myeloid infiltrate was less suppressive to T cells. Transcriptional analysis of tumor-specific CD8 T cells showed that anti-VISTA therapy induced T cell pathways highly distinct from the anti-exhaustion effects of anti-PD-1 therapy.

Conclusions These data document the unique and complementary impact of targeting VISTA in contrast to PD-1 and CTLA-4 in both the myeloid and T cell lineages. These mechanistic insights strongly support the use of anti-VISTA to overcome the checkpoint resistance seen in contemporary treatments involving PD-1.

Ethics Approval All mouse studies described in this work were carried out in accordance with the principles of the Guide for the Care and Use of Animals and were approved by the Institutional Animal Care and Use Committee of Dartmouth College, NH, USA (protocol 2012).

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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