Wong et al. demonstrated that chronic IFNγ exposure upregulated the IFNγ target gene product poly-ADP ribosyl polymerase 14 (PARP14) via the IFNγ-STAT1 axis, and drove resistance to anti-PD-1 therapy. PARP14 inhibition promoted pro-inflammatory phenotypes in both CD4+ and CD8+ T cells, and reduced Tregs and suppressive factors, such as TGFβ and IL-10. PARP14 depletion in tumor cells reversed adaptive resistance to anti-PD-1 therapy and chronic IFNγ-driven immune regulatory effects. PARP14 inhibition remodeled the TME, induced an inflammatory response, and potentiated the immunostimulatory effect of anti-PD-1 in chronic IFNγ-induced immunosuppressive TMEs.
Contributed by Shishir Pant
ABSTRACT: Resistance mechanisms to immune checkpoint blockade therapy (ICBT) limit its response duration and magnitude. Paradoxically, Interferon γ (IFNγ), a key cytokine for cellular immunity, can promote ICBT resistance. Using syngeneic mouse tumour models, we confirm that chronic IFNγ exposure confers resistance to immunotherapy targeting PD-1 (α-PD-1) in immunocompetent female mice. We observe upregulation of poly-ADP ribosyl polymerase 14 (PARP14) in chronic IFNγ-treated cancer cell models, in patient melanoma with elevated IFNG expression, and in melanoma cell cultures from ICBT-progressing lesions characterised by elevated IFNγ signalling. Effector T cell infiltration is enhanced in tumours derived from cells pre-treated with IFNγ in immunocompetent female mice when PARP14 is pharmacologically inhibited or knocked down, while the presence of regulatory T cells is decreased, leading to restoration of α-PD-1 sensitivity. Finally, we determine that tumours which spontaneously relapse in immunocompetent female mice following α-PD-1 therapy upregulate IFNγ signalling and can also be re-sensitised upon receiving PARP14 inhibitor treatment, establishing PARP14 as an actionable target to reverse IFNγ-driven ICBT resistance.
Author Info: (1) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester,
Author Info: (1) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. (2) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. (3) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. (4) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. (5) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (6) Cancer Data Science Laboratory, National Cancer Institute, Bethesda, MD, 20814, USA. (7) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. (8) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. (9) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. (10) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (11) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (12) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (13) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (14) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (15) Ribon Therapeutics Inc., 35 Cambridge Park Drive, Suite 300, Cambridge, MA, 02140, USA. (16) Ribon Therapeutics Inc., 35 Cambridge Park Drive, Suite 300, Cambridge, MA, 02140, USA. (17) Ribon Therapeutics Inc., 35 Cambridge Park Drive, Suite 300, Cambridge, MA, 02140, USA. (18) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (19) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, M20 4BX, UK. (20) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. (21) Patricia E. Rao Consulting, Acton, MA, 01720, USA. (22) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester, UK. (23) Ribon Therapeutics Inc., 35 Cambridge Park Drive, Suite 300, Cambridge, MA, 02140, USA. (24) Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, M13 9PT, UK. adam.hurlstone@manchester.ac.uk. Lydia Becker Institute of Immunology, The University of Manchester, Manchester, M13 9PT, UK. adam.hurlstone@manchester.ac.uk.
