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T cell receptor sequencing of early-stage breast cancer tumors identifies altered clonal structure of the T cell repertoire

  1. Stephen R. Quakea,c,d,1
  1. aDepartment of Bioengineering, Stanford University, Stanford, CA 94305;
  2. bDepartment of Surgery, Stanford University School of Medicine, Stanford, CA 94305;
  3. cDepartment of Applied Physics, Stanford University, Stanford, CA 94305;
  4. dChan Zuckerberg Biohub, San Francisco, CA 94518
  1. Contributed by Stephen R. Quake, October 14, 2017 (sent for review August 7, 2017; reviewed by Ramy Arnaout and Curtis G. Callan, Jr.)

Significance

The recent advances in cancer immunotherapy motivated us to investigate the clonal structure of the T cell receptor repertoire in breast tumors, normal breast, and blood in the same individuals. We found quantitatively distinct clonal structures in all three tissues, which enabled us to predict whether tissue is normal or tumor solely by comparing the repertoire of the tissue with blood. T cell receptor sequences shared between patients’ tumors are rare and, in general, do not appear to be specific to the cancer.

Abstract

Tumor-infiltrating T cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T cell beta-chain repertoire in 16 patients with early-stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing ~2.5-fold greater density of T cells and higher clonality compared with normal breast. The clonal structure of T cells in blood and normal breast is more similar than between blood and tumor, and could be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T cell sequences overlap between tissue and blood from the same patient, including ~50% of T cells between tumor and normal breast. Both tumor and normal breast contain high-abundance “enriched” sequences that are absent or of low abundance in the other tissue. Many of these T cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T cells in both tumor and normal breast. Enriched T cell sequences are typically unique to each patient, but a subset is shared between many different patients. We show that many of these are commonly generated sequences, and thus unlikely to play an important role in the tumor microenvironment.

Footnotes

  • ?1To whom correspondence should be addressed. Email: quake{at}stanford.edu.
  • Author contributions: J.F.B., S.S.J., and S.R.Q. designed research; J.F.B., A.J.W., N.H.C., V.R.H., and F.M.D. performed research; J.F.B. contributed new reagents/analytic tools; J.F.B., S.S.J., and S.R.Q. analyzed data; and J.F.B., S.S.J., and S.R.Q. wrote the paper.

  • Reviewers: R.A., Beth Israel Deaconess Medical Center; and C.G.C., Princeton University.

  • The authors declare no conflict of interest.

  • Data deposition: The data reported in this paper have been deposited in the immuneACCESS database, http://www.danielhellerman.com/pub/beausang-2017-pnas.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1713863114/-/DCSupplemental.

Online Impact

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