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Deep Sequencing of T-cell Receptor DNA as a Biomarker of Clonally Expanded TILs in Breast Cancer after Immunotherapy.
- Source :
-
Cancer immunology research [Cancer Immunol Res] 2016 Oct; Vol. 4 (10), pp. 835-844. Date of Electronic Publication: 2016 Sep 01. - Publication Year :
- 2016
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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 × 10 <superscript>6</superscript> 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.<br />Competing Interests: Juanda Yuan and Jedd Wolchok are listed on the patent of the ImmunoSEQ assay. Harlan Robins receives royalties, has partial ownership of, and serves as a paid consultant for Adaptive Biotechnologies. Ryan Emerson is employed by, and has stock ownership in, Adaptive Biotechnologies. James Alison receive royalties from Bristol Myers Squibb. Heather McArthur and Jedd Wolchok receives research funding from Bristol Myers Squibb.<br /> (©2016 American Association for Cancer Research.)
- Subjects :
- Antineoplastic Agents, Immunological therapeutic use
Biopsy
Breast Neoplasms genetics
Breast Neoplasms pathology
Breast Neoplasms therapy
Combined Modality Therapy
Cryosurgery
DNA, Neoplasm genetics
Feasibility Studies
Female
High-Throughput Nucleotide Sequencing methods
Humans
Ipilimumab therapeutic use
Leukemic Infiltration
Lymphocyte Count
Mastectomy methods
Neoplasm Staging
Pilot Projects
Receptors, Antigen, T-Cell, alpha-beta immunology
Sequence Analysis, DNA methods
Biomarkers, Tumor genetics
Breast Neoplasms immunology
Immunotherapy methods
Lymphocytes, Tumor-Infiltrating immunology
Receptors, Antigen, T-Cell, alpha-beta genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2326-6074
- Volume :
- 4
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Cancer immunology research
- Publication Type :
- Academic Journal
- Accession number :
- 27587469
- Full Text :
- https://doi.org/10.1158/2326-6066.CIR-16-0013