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2015 ; 3
(6
): 610-9
Nephropedia Template TP
Park SS
; Dong H
; Liu X
; Harrington SM
; Krco CJ
; Grams MP
; Mansfield AS
; Furutani KM
; Olivier KR
; Kwon ED
Cancer Immunol Res
2015[Jun]; 3
(6
): 610-9
PMID25701325
show ga
We investigated the influence of PD-1 expression on the systemic antitumor
response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR)
in preclinical melanoma and renal cell carcinoma models. We compared the
SABR-induced antitumor response in PD-1-expressing wild-type (WT) and
PD-1-deficient knockout (KO) mice and found that PD-1 expression compromises the
survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice
survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days.
Similarly, PD-1-blocking antibody in WT mice was able to recapitulate
SABR-induced antitumor responses observed in PD-1 KO mice and led to increased
survival. The combination of SABR plus PD-1 blockade induced near complete
regression of the irradiated primary tumor (synergistic effect), as opposed to
SABR alone or SABR plus control antibody. The combination of SABR plus PD-1
blockade therapy elicited a 66% reduction in size of nonirradiated, secondary
tumors outside the SABR radiation field (abscopal effect). The observed abscopal
effect was tumor specific and was not dependent on tumor histology or host
genetic background. The CD11a(high) CD8(+) T-cell phenotype identifies a
tumor-reactive population, which was associated in frequency and function with a
SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR
induces an abscopal tumor-specific immune response in both the irradiated and
nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of
SABR and PD-1 blockade has the potential to translate into a potent immunotherapy
strategy in the management of patients with metastatic cancer.
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