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Radiotherapy induces responsiveness of a resistant mammary carcinoma to PD-1 blockade

  • Julie Diamond1,
  • Karsten Pilones1,
  • Joseph Aryankalayil1,
  • Ralph Vatner1,
  • Silvia Formenti1 and
  • Sandra Demaria1
Journal for ImmunoTherapy of Cancer20142(Suppl 3):P159

https://doi.org/10.1186/2051-1426-2-S3-P159

Published: 6 November 2014

Keywords

Immunogenic TumorActivation Marker CD69Dual BenefitTumor EpitopeShow Tumor Regression

Background

We've previously shown that radiotherapy (RT) converts poorly immunogenic tumors resistant to antibodies (mAbs) against the immune checkpoint receptor CTLA-4 into susceptible ones (Demaria et al., 2005; Dewan et al., 2009). Programmed death-1 (PD-1) is another immune checkpoint receptor upregulated on T-cells shortly after activation and expressed at high levels on exhausted T-cells. Anti-PD-1 mAbs have shown marked clinical activity in some cancer patients, but the majority does not respond. Here we tested the hypothesis that RT can sensitize poorly immunogenic tumors to anti-PD-1.

Methods

BALB/c mice were subcutaneously inoculated with syngeneic, poorly immunogenic TSA breast carcinoma cells on day0. When tumors became palpable, mice were randomly assigned to one of four treatment groups: control, RT, anti-PD-1 and RT+anti-PD-1. Local RT was administered to the tumor in three 8Gy fractions on days 13, 14, 15. PD-1-blocking mAb RMP1-14 was given on day15 and every 4 days thereafter. Mice were followed for tumor growth. In a separate experiment, mice were euthanized on day20 to characterize tumor-infiltrating lymphocytes (TILs) and development of CD8+ T cells specific for tumor epitope, AH1, using pentamer analysis.

Results

Expression of activation markers CD69 and CD137 was increased in CD8+ TILs from mice treated with RT, while RMP1-14 was ineffective (64%-RT or 70%-RT+RMP1-14 compared to 42%-control and 47%-RMP1-14, p < 0.001). RT-treated mice also showed significant increase in CD8+ TILs expressing high levels of PD-1 (CD8+PD-1hi) (67% vs 36%, p<0.01). Importantly, PD-1 ligands, PDL-1/2, were upregulated by RT on TSA cells and tumor-infiltrating myeloid cells, suggesting PD-1's interaction with its ligands may limit RT-activated anti-tumor T-cell activity. Consistent with this hypothesis, RMP1-14 alone had no effect on tumor growth; RT delayed growth (p < 0.01), but only 1/6 mice showed tumor regression, whereas all mice receiving RT+RMP1-14 completely rejected tumors by day 25. In spleen, RMP1-14 had no effect on AH1-specific CD8+ T-cells (1.8% vs 1.7%-control) while RT significantly expanded this population (2.9%, p < 0.05). RT+RMPI-14, however, demonstrated the highest increase (4.6%, p < 0.05 vs. all other groups).

Conclusion

These results suggest dual benefits of anti-PD-1 when used in combination with RT. PD-1 blockade enhances RT-induced T cell priming, possibly by decreasing the TCR activation threshold. Simultaneously, anti-PD-1 recovers T-cell effector activity in the tumor by abrogating the inhibitory signals mediated by RT-induced PD-1 ligands. Data strongly supports testing this combination in the clinic.

Supported by the Breast Cancer Alliance (Exceptional Project Award)

Authors’ Affiliations

(1)
NYU School of Medicine, New York, USA

Copyright

© Diamond et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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