Professor University of Alabama, Birmingham Birmingham, Alabama, United States
Disclosure(s):
Lewis Z. Shi, MD, PhD: No financial relationships to disclose
Introduction/Rationale: Immune checkpoint blockers (ICB, e.g., anti-CTLA-4/D-1) have become a major pillar of cancer care for patients with advanced solid tumors. However, therapeutic resistance has become a bottleneck issue, limiting their overall efficacy to a fraction of patients. Concerted efforts from others and us have identified loss of IFN-g signaling as a major tumor-intrinsic resistance to ICBs in various types of tumors (melanoma, bladder cancer, and colorectal cancer). Therefore, identifying approaches to overcome this resistance will expand the patient population that can benefit from ICBs, a poorly explored area. Given the immunomodulatory effects of radiation (RT) and its ability to re-sensitize tumors to ICBs independent of IFN-g-driven tumor killing, we reason that RT represents an effective strategy to treat ICB-resistant tumors lacking IFN-g signaling (IFNgR1-KO).
Methods: We formulated an immunogenic hypofractionated RT regimen (hypo-RT) to treat mice bearing IFNgR1-KO tumors, +/- ICBs. To achieve long-term cure, we employed Ruxolitinib (Ruxo), a targeted therapy for IFNgR1-KO tumors and a radiosensitizer that we previously described. Isolated TILs were analyzed by multi-color flow cytometry to shed light on the underlying mechanisms.
Results: Hypo-RT enhanced T cell infiltration, increased cytokine production, and when combined with anti-CTLA-4, improved the progression-free survival compared to RT alone, suggesting re-sensitization of IFNgR1-KO tumors to ICB. Hypo-RT significantly boosted therapeutic effects of Ruxolitinib, a targeted therapy for IFNgR1-KO tumors (2022 Nat. Comms.) Vice versa, Ruxolitinib enhanced RT-driven tumor suppression (P=0.08). Interestingly, hypo-RT depleted FoxP3+ Treg in wild-type but not IFNgR1-KO tumors, revealing a heretofore unknown role of tumor IFNgR1 signaling in RT-driven Treg depletion, which can be overcome by Ruxolitinib.
Conclusion: Hypo-RT is an effective strategy to bypass tumor-intrinsic ICB resistance in IFNgR1-KO tumors.
