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Radiotherapy induces responses of lung cancer to CTLA-4 blockade
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DOI：10.1038/s41591-018-0232-2.png)
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Abstract
En 中文
Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma(1-3), but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor(4-6). The latter is essential for achieving abscopal responses in murine cancers(6). The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy(7,8). Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-beta after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.
Keywords:
NEURAL-NETWORKS
SOLID TUMORS
CELL
RADIATION
SEQ
SUPPRESSION
REPERTOIRE
IPILIMUMAB
SURVIVAL
MUTATION
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