Radiotherapy induces responses of lung cancer to CTLA-4 blockade

Silvia C. Formenti, Nils Petter Rudqvist, Encouse Golden, Benjamin Cooper, Erik Wennerberg, Claire Lhuillier, Claire Vanpouille-Box, Kent Friedman, Lucas Ferrari de Andrade, Kai W. Wucherpfennig, Adriana Heguy, Naoko Imai, Sacha Gnjatic, Ryan O. Emerson, Xi Kathy Zhou, Tuo Zhang, Abraham Chachoua, Sandra Demaria

Research output: Contribution to journalArticlepeer-review

552 Scopus citations


Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma1–3, 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 tumor4–6. The latter is essential for achieving abscopal responses in murine cancers6. 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 chemotherapy7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β 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.

Original languageEnglish
Pages (from-to)1845-1851
Number of pages7
JournalNature Medicine
Issue number12
StatePublished - 1 Dec 2018


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