Radiotherapy and CTLA-4 blockade shape the tcr repertoire of tumor-infiltrating t cells

Nils Petter Rudqvist, Karsten A. Pilones, Claire Lhuillier, Erik Wennerberg, John William Sidhom, Ryan O. Emerson, Harlan S. Robins, Jonathan P Schneck, Silvia C. Formenti, Sandra Demaria

Research output: Contribution to journalArticle

Abstract

Immune checkpoint inhibitors activate T cells to reject tumors. Unique tumor mutations are key T-cell targets, but a comprehensive understanding of the nature of a successful antitumor T-cell response is lacking. To investigate the T-cell receptor (TCR) repertoire associated with treatment success versus failure, we used a well-characterized mouse carcinoma that is rejected by CD8 T cells in mice treated with radiotherapy (RT) and anti-CTLA-4 in combination, but not as monotherapy, and comprehensively analyzed tumor-infiltrating lymphocytes (TILs) by high-throughput sequencing of the TCRB CDR3 region. The combined treatment increased TIL density and CD8/CD4 ratio. Assessment of the frequency of T-cell clones indicated that anti-CTLA-4 resulted in fewer clones and a more oligoclonal repertoire compared with untreated tumors. In contrast, RT increased the CD8/CD4 ratio and broadened the TCR repertoire, and when used in combination with anti-CTLA-4, these selected T-cell clones proliferated. Hierarchical clustering of CDR3 sequences showed a treatment-specific clustering of TCRs that were shared by different mice. Abundant clonotypes were commonly shared between animals and yet treatment-specific. Analysis of amino-acid sequence similarities revealed a significant increase in the number and richness of dominant CDR3 motifs in tumors treated with RT \+ anti-CTLA-4 compared with control. The repertoire of TCRs reactive with a single tumor antigen recognized by CD8\+ T cells was heterogeneous but highly clonal, irrespective of treatment. Overall, data support a model whereby a diverse TCR repertoire is required to achieve tumor rejection and may underlie the synergy between RT and CTLA-4 blockade.

Original languageEnglish (US)
Pages (from-to)139-150
Number of pages12
JournalCancer immunology research
Volume6
Issue number2
DOIs
StatePublished - Feb 1 2018

ASJC Scopus subject areas

  • Immunology
  • Cancer Research

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    Rudqvist, N. P., Pilones, K. A., Lhuillier, C., Wennerberg, E., Sidhom, J. W., Emerson, R. O., Robins, H. S., Schneck, J. P., Formenti, S. C., & Demaria, S. (2018). Radiotherapy and CTLA-4 blockade shape the tcr repertoire of tumor-infiltrating t cells. Cancer immunology research, 6(2), 139-150. https://doi.org/10.1158/2326-6066.CIR-17-0134