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Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer

Jorge Blando, Anu Sharma, Maria Gisela Higa, Hao Zhao, Luis Vence, Shalini S. Yadav, Jiseong Kim, Alejandro M. Sepulveda, Michael Sharp, Anirban Maitra, Jennifer Wargo, Michael Tetzlaff, Russell Broaddus, Matthew H. G. Katz, Gauri R. Varadhachary, Michael Overman, Huamin Wang, Cassian Yee, Chantale Bernatchez, Christine Iacobuzio-Donahue, Sreyashi Basu, James P. Allison, and Padmanee Sharma
PNAS January 29, 2019 116 (5) 1692-1697; published ahead of print January 29, 2019 https://doi.org/10.1073/pnas.1811067116
Jorge Blando
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
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Anu Sharma
bDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Maria Gisela Higa
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
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Hao Zhao
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
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Luis Vence
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
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Shalini S. Yadav
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
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Jiseong Kim
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
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Alejandro M. Sepulveda
cJanssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19477;
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Michael Sharp
cJanssen Oncology Therapeutic Area, Janssen Research and Development, LLC, Pharmaceutical Companies of Johnson & Johnson, Spring House, PA 19477;
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Anirban Maitra
dDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;eDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Jennifer Wargo
fDepartment of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Michael Tetzlaff
dDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Russell Broaddus
dDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Matthew H. G. Katz
fDepartment of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Gauri R. Varadhachary
gDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Michael Overman
gDepartment of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Huamin Wang
dDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Cassian Yee
hDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Chantale Bernatchez
hDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;
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Christine Iacobuzio-Donahue
iDavid Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065;
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Sreyashi Basu
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;
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James P. Allison
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;jDepartment of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
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  • For correspondence: jallison@mdanderson.orgpadsharma@mdanderson.org
Padmanee Sharma
aThe Immunotherapy Platform, The University of Texas MD Anderson Cancer Center, Houston, TX 77054;bDepartment of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030;jDepartment of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030
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  • For correspondence: jallison@mdanderson.orgpadsharma@mdanderson.org
  1. Contributed by James P. Allison, November 30, 2018 (sent for review July 19, 2018; reviewed by Nina Bhardwaj and Aatur D. Singhi)

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Significance

The study demonstrates that V-domain immunoglobulin suppressor of T cell activation (VISTA) is an immune checkpoint that is preferentially expressed at higher levels in pancreatic cancer. The study gives a detailed analysis of immune infiltration in primary and metastatic pancreatic tumors compared with melanoma, which differs in its tumor/stromal distribution. Our data indicate that human pancreatic tumors express CD68+ macrophages and highlight the inhibitory checkpoint molecule VISTA as a potential immunotherapeutic target in pancreatic cancer.

Abstract

Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68+ macrophages and VISTA+ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.

  • pancreatic cancer
  • immune monitoring
  • immune checkpoints
  • immunopathology
  • immune infiltrate

Footnotes

  • ↵1J.B. and A.S. contributed equally to this work.

  • ↵2To whom correspondence may be addressed. Email: jallison{at}mdanderson.org or padsharma{at}mdanderson.org.
  • Author contributions: P.S. and J.P.A. designed research and supervised the study; A.M., J.W., G.R.V., M.O., C.Y., C.B., C.I.-D., J.P.A., and P.S. managed patients and provided analytical and material support; A.M.S. and M.S. contributed new reagents/analytic tools; J.B., A.S., M.G.H., J.K., and S.B. performed research; J.B., A.S., H.Z., L.V., S.S.Y., S.B., J.P.A., and P.S. analyzed data; J.B., M.T., R.B., M.H.G.K., and H.W. reviewed pathology and immunohistochemistry data; and J.B., A.S., S.S.Y., and P.S. wrote the paper.

  • Reviewers: N.B., Mt. Sinai School of Medicine; and A.D.S., University of Pittsburgh School of Medicine.

  • Conflict of interest statement: J.P.A. is an inventor and recipient of royalties from intellectual property licensed to Bristol-Meyer Squibb, Merck, and Jounce. He is a member of the scientific advisory board for Jounce Therapeutics, Neon Therapeutics, Amgen, Apricity, BioAlta, Forty-Seven, Tvardi Therapeutics, TapImmune, ImaginAB, Codiak Biosciences, and Marker Therapeutics. J.P.A. and P.S. own a patent licensed to Jounce Therapeutics. P.S. serves as a consultant for Constellation, Jounce Therapuetics, Kite Pharma, Neon Therapeutics, BioAtla, Pieris Pharmaceuticals, Oncolytics Biotech, Merck, BioMx, Forty-Seven, Polaris, Apricity, Marker Therapeutics, Codiak, ImaginAB, and TapImmune. She also has stock ownership in Jounce, Neon Therapeutics, Constellation, Oncolytics, BioAtlanta, Forty-Seven, Apricity, Polaris, Marker Therapeutics, Codiak, ImaginAB, and TapImmune. A.S. is an employee of Janssen.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1811067116/-/DCSupplemental.

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Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer
Jorge Blando, Anu Sharma, Maria Gisela Higa, Hao Zhao, Luis Vence, Shalini S. Yadav, Jiseong Kim, Alejandro M. Sepulveda, Michael Sharp, Anirban Maitra, Jennifer Wargo, Michael Tetzlaff, Russell Broaddus, Matthew H. G. Katz, Gauri R. Varadhachary, Michael Overman, Huamin Wang, Cassian Yee, Chantale Bernatchez, Christine Iacobuzio-Donahue, Sreyashi Basu, James P. Allison, Padmanee Sharma
Proceedings of the National Academy of Sciences Jan 2019, 116 (5) 1692-1697; DOI: 10.1073/pnas.1811067116

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Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer
Jorge Blando, Anu Sharma, Maria Gisela Higa, Hao Zhao, Luis Vence, Shalini S. Yadav, Jiseong Kim, Alejandro M. Sepulveda, Michael Sharp, Anirban Maitra, Jennifer Wargo, Michael Tetzlaff, Russell Broaddus, Matthew H. G. Katz, Gauri R. Varadhachary, Michael Overman, Huamin Wang, Cassian Yee, Chantale Bernatchez, Christine Iacobuzio-Donahue, Sreyashi Basu, James P. Allison, Padmanee Sharma
Proceedings of the National Academy of Sciences Jan 2019, 116 (5) 1692-1697; DOI: 10.1073/pnas.1811067116
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