Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade

TLDR

Radiotherapy is a major treatment for common cancers, yet many patients experience local recurrence and metastatic disease. The study proposes that, with careful scheduling, combining radiotherapy with PD‑1/PD‑L1 blockade may immediately improve clinical outcomes. Mechanistic work showed that IFNγ from CD8+ T cells drives PD‑L1 upregulation after fractionated radiotherapy, and that concurrent anti‑PD‑L1 antibody administration is required for therapeutic benefit. Low‑dose fractionated radiotherapy induces PD‑L1 on tumor cells, but concurrent anti‑PD‑1/PD‑L1 antibodies elicit strong CD8+ T‑cell responses that improve local control, long‑term survival, and generate tumor‑antigen‑specific memory, demonstrating that adaptive resistance can be overcome by timely checkpoint blockade. Published in Cancer Research 74(19):5458–68, ©2014 AACR.

Abstract

Abstract Radiotherapy is a major part in the treatment of most common cancers, but many patients experience local recurrence with metastatic disease. In evaluating response biomarkers, we found that low doses of fractionated radiotherapy led to PD-L1 upregulation on tumor cells in a variety of syngeneic mouse models of cancer. Notably, fractionated radiotherapy delivered in combination with αPD-1 or αPD-L1 mAbs generated efficacious CD8+ T-cell responses that improved local tumor control, long-term survival, and protection against tumor rechallenge. These favorable outcomes were associated with induction of a tumor antigen–specific memory immune response. Mechanistic investigations showed that IFNγ produced by CD8+ T cells was responsible for mediating PD-L1 upregulation on tumor cells after delivery of fractionated radiotherapy. Scheduling of anti–PD-L1 mAb was important for therapeutic outcome, with concomitant but not sequential administration with fractionated radiotherapy required to improve survival. Taken together, our results reveal the mechanistic basis for an adaptive response by tumor cells that mediates resistance to fractionated radiotherapy and its treatment failure. With attention to scheduling, combination immunoradiotherapy with radiotherapy and PD-1/PD-L1 signaling blockade may offer an immediate strategy for clinical evaluation to improve treatment outcomes. Cancer Res; 74(19); 5458–68. ©2014 AACR.