Radiation therapy can enhance the systemic antitumour responses (abscopal responses) induced by anti-CTLA4 antibodies, as shown in preclinical studies. However, it was unclear how effective these induced systemic responses are against tumours unresponsive to CTLA4 blockade alone. Now, Formenti, Demaria and colleagues report in Nature Medicine that a combination of radiotherapy and CTLA4 blockade induced systemic antitumour T cells in patients with non-small-cell lung cancer (NSCLC) who did not respond to CTLA4 blockade alone, possibly through radiotherapy-induced upregulation of a neoantigen recognized by expanded T cell clones.

Credit: Lara Crow/Springer Nature Limited

Thirty-nine patients with NSCLC whose tumours had progressed after prior systemic treatment were enrolled in a clinical trial to evaluate radiotherapy in combination with the anti-CTLA4 antibody ipilimumab. Of the 21 patients who completed the treatment, 2 patients had a complete response, 5 had a partial response and 5 had stable disease.

The authors compared levels of various soluble markers and immune cells in the tumour tissue and peripheral blood of the patients before and after treatment. Notably, radiotherapy induction of IFNβ correlated with an abscopal response to the combination therapy — in the patients who responded to treatment, serum IFNβ levels significantly increased at day 22 (after radiation therapy); those who had stable disease had a significant IFNβ increase but it was less than those who responded; and patients who progressed had no significant IFNβ increase.

Next, T cell receptor (TCR) sequencing established that several T cell clones were expanded in peripheral blood at day 22 compared with baseline in patients with complete or partial responses compared with patients with stable disease or who progressed. Furthermore, levels of IFNβ after radiotherapy combined with the changes in the TCR repertoire had the highest predictive value of response.

Examination of the tumour specificity of the expanded CD8+ T cell clones in one patient with a complete response indicated that this patient had tumour-infiltrating lymphocytes that matched the expanded clones. The authors also identified two expanded T cell clones in the blood of this patient, both of which recognized a neoantigen derived from a protein thought to be upregulated during radiotherapy, karyopherin α2.

Thus, the authors hypothesize that radiotherapy may increase expression of immunogenic mutations in the tumour, leading to the activation of T cells that induce IFNβ, suggesting a possible future role for a combination therapy with ipilimumab and radiotherapy.

This article is modified from the original in Nat. Rev. Cancer (https://doi.org/10.1038/s41568-018-0094-4).