| Title: |
Sequential JAK inhibition enhances anti-tumor immunity after combined anti-PD-1 and anti-CTLA4 |
| Authors: |
Arias-Badia, Marcel; Chen, PeiXi; Lwin, Yee May; Srinath, Aahir; Lyu, Aram; Fan, Zenghua; Kwek, Serena S; Luong, Diamond N; Setayesh, Ali; Sakamoto, Mason; Clark, Matthew; Lea, Averey; Wolters, Rachel M; Goodearl, Andrew; Harding, Fiona A; Gorman, Jacob V; Ritacco, Wendy; Fong, Lawrence |
| Source: |
JCI Insight, vol 10, iss 7 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2025 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
32 Biomedical and Clinical Sciences (for-2020); 3211 Oncology and Carcinogenesis (for-2020); 3204 Immunology (for-2020); Immunotherapy (rcdc); Cancer (rcdc); 5.1 Pharmaceuticals (hrcs-rac); Cancer (hrcs-hc); Animals (mesh); Mice (mesh); Immune Checkpoint Inhibitors (mesh); Programmed Cell Death 1 Receptor (mesh); Interferon-gamma (mesh); CTLA-4 Antigen (mesh); Janus Kinase Inhibitors (mesh); Female (mesh); Cell Line; Tumor (mesh); Humans (mesh); T-Lymphocytes (mesh); Janus Kinase 1 (mesh); Mice; Inbred C57BL (mesh); Neoplasms (mesh); Imidazoles (mesh); Signal Transduction (mesh); Aminopyridines (mesh); Pyrroles (mesh); Cancer immunotherapy; Cellular immune response; Drug therapy |
| Description: |
While immune checkpoint inhibition (CPI) has reshaped cancer treatment, the majority of patients with cancer do not benefit from this approach, which can also cause immune-related adverse events. Induction of IFN-γ responses is thought be necessary for antitumor immunity, but growing evidence also implicates IFN-γ as a tumor-intrinsic mediator of CPI resistance. CPI-induced IFN-γ mediates activation-induced cell death in T cells as an immune-intrinsic mechanism of resistance. In this study, we found that transient block of IFN-γ signaling through administration of the JAK1 inhibitor ABT-317 enhanced antitumor T cell responses with CPI in preclinical models. Importantly, sequential but not concomitant ABT-317 treatment led to significantly reduced toxicity and improved tumor efficacy. Sequential treatment reduced activation-induced T cell death and enhanced expansion of tumor-reactive T cell subsets with increased effector function in vivo and ex vivo. Only CPI in combination with ABT-317 also enhanced memory responses by protecting mice from tumor rechallenge. These results demonstrate that JAK inhibition within a discrete time window following CPI addresses an immune-intrinsic mechanism of therapeutic resistance. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt8k61v529; https://escholarship.org/uc/item/8k61v529; https://escholarship.org/content/qt8k61v529/qt8k61v529.pdf |
| DOI: |
10.1172/jci.insight.187921 |
| Availability: |
https://escholarship.org/uc/item/8k61v529; https://escholarship.org/content/qt8k61v529/qt8k61v529.pdf; https://doi.org/10.1172/jci.insight.187921 |
| Rights: |
CC-BY |
| Accession Number: |
edsbas.6D8C47F0 |
| Database: |
BASE |