Journal Article
. 2016 Sep; 4(10):835-844.
doi: 10.1158/2326-6066.CIR-16-0013.

Deep Sequencing of T-cell Receptor DNA as a Biomarker of Clonally Expanded TILs in Breast Cancer after Immunotherapy

David B Page 1 Jianda Yuan 2 David Redmond 3 Y Hanna Wen 2 Jeremy C Durack 2 Ryan Emerson 4 Stephen Solomon 2 Zhiwan Dong 2 Phillip Wong 2 Christopher Comstock 2 Adi Diab 5 Janice Sung 2 Majid Maybody 2 Elizabeth Morris 2 Edi Brogi 2 Monica Morrow 2 Virgilio Sacchini 2 Olivier Elemento 6 Harlan Robins 7 Sujata Patil 2 James P Allison 5 Jedd D Wolchok 8 Clifford Hudis 8 Larry Norton 8 Heather L McArthur 8 
Affiliations
  • PMID: 27587469
  •     23 References
  •     58 citations

Abstract

In early-stage breast cancer, the degree of tumor-infiltrating lymphocytes (TIL) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, T-cell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 106 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared with monotherapy, cryoablation plus ipilimumab was associated with numerically greater numbers of peripheral blood and intratumoral T-cell clones expanding robustly following therapy. In conclusion, TCR sequencing correlates with H&E lymphocyte scoring and provides additional information on clonal diversity. These findings support further study of the use of TCR sequencing as a biomarker for T-cell responses to therapy and for the study of cryoimmunotherapy in early-stage breast cancer. Cancer Immunol Res; 4(10); 835-44. ©2016 AACR.

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