Open AccessInhibition of Polyamine Biosynthesis Using Difluoromethylornithine Acts as a Potent Immune Modulator and Displays Therapeutic Synergy With PD-1-blockade
Author(s) -
Parker Dryja,
Carrie L. Fisher,
Patrick M. Woster,
Eric Bartee
Publication year - 2021
Publication title -
journal of immunotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.805
H-Index - 92
eISSN - 1537-4513
pISSN - 1524-9557
DOI - 10.1097/cji.0000000000000379
Subject(s) - blockade , pharmacology , cancer research , immune system , polyamine , cytokine , in vivo , immune checkpoint , tumor microenvironment , medicine , proinflammatory cytokine , immunotherapy , immunology , biology , chemistry , inflammation , biochemistry , receptor , microbiology and biotechnology
Polyamines are known to play a significant role in cancer progression and treatment using difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, has shown some clinical promise. It is interesting to note that, while DFMO is directly cytostatic in vitro, recent work has suggested that it achieves its antitumor efficacy in vivo by enhancing adaptive antitumor immune responses. On the basis of these data, we hypothesized that DFMO might act as an immune sensitizer to increase tumor responsiveness to checkpoint blockade. To test this hypothesis, we treated tumors with DFMO, in either the presence or absence of additional PD-1 blockade, and subsequently analyzed their immunological and therapeutic responses. Our data demonstrates that treatment with DFMO significantly enhances both the viability and activation status of intratumoral CD8+ T cells, most likely through an indirect mechanism. When combined with PD-1 blockade, this increased viability resulted in unique proinflammatory cytokine profiles and transcriptomes within the tumor microenvironment and improved therapeutic outcomes. Taken together, these data suggest that DFMO might represent a potential immunomodulatory agent that can enhance current PD-1-based checkpoint therapies.