Supplemental Figures 1 - 7 from Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade

Dovedi, Simon J.; Adlard, Amy L.; Lipowska-Bhalla, Grazyna; McKenna, Conor; Jones, Sherrie; Cheadle, Eleanor J.; Stratford, Ian J.; Poon, Edmund; Morrow, Michelle; Stewart, Ross; Jones, Hazel; Wilkinson, Robert W.; Honeychurch, Jamie; Illidge, Tim M.

doi:10.1158/0008-5472.22403754.v1

Supplemental Figures 1 - 7 from Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade

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posted on 2023-03-30, 22:47 authored by Simon J. Dovedi, Amy L. Adlard, Grazyna Lipowska-Bhalla, Conor McKenna, Sherrie Jones, Eleanor J. Cheadle, Ian J. Stratford, Edmund Poon, Michelle Morrow, Ross Stewart, Hazel Jones, Robert W. Wilkinson, Jamie Honeychurch, Tim M. Illidge

Supplemental figure 1: Gating strategy for determining tumor cell PD-L1 expression. Supplemental figure 2: Impact of low-dose fractionated RT on PD-L1 expression by CD11b+GR1Hi cells. Supplemental figure 3: Dual blockade of PD-1 and PD-L1 does not further enhance efficacy of RT combination. Supplemental figure 4: Blockade of PD-1 / PD-L1 in combination with local RT is well tolerated in mice. Supplemental figure 5: PD-1 / PD-L1 blockade does not directly sensitise tumor cells to RT. Supplemental figure 6: Scheduling of RT and anti-PD-L1 is critical for anti-tumor activity. Supplemental figure 7: Only acute administration of anti-PD-L1 mAb may be required to achieve efficacy when delivered in combination with RT.

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ARTICLE 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.

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Immunology Immune responses to cancer Tumor resistance to immune response Immunotherapy Antibody immunotherapy Radiation Oncology Combined modality therapies Radiobiology Modulators of radiation response Radiation and tumor microenvironment

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Supplemental Figures 1 - 7 from Acquired Resistance to Fractionated Radiotherapy Can Be Overcome by Concurrent PD-L1 Blockade

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