Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Peter Bailey, David K. Chang, Marie Andreé Forget, Francis A San Lucas, Hector A. Alvarez, Cara Haymaker, Chandrani Chattopadhyay, Sun Hee Kim, Suhendan Ekmekcioglu, Elizabeth A. Grimm, Andrew V. Biankin, Patrick Hwu, Anirban Maitra, Jason Roszik

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Abstract

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues.

Original languageEnglish (US)
Article number35848
JournalScientific Reports
Volume6
DOIs
StatePublished - Oct 20 2016
Externally publishedYes

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ASJC Scopus subject areas

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Cite this

Bailey, P., Chang, D. K., Forget, M. A., Lucas, F. A. S., Alvarez, H. A., Haymaker, C., Chattopadhyay, C., Kim, S. H., Ekmekcioglu, S., Grimm, E. A., Biankin, A. V., Hwu, P., Maitra, A., & Roszik, J. (2016). Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma. Scientific Reports, 6, [35848]. https://doi.org/10.1038/srep35848