Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites1. However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8+ T cells in ovarian and colorectal cancer—two tumor types for which T cell infiltrates form a positive prognostic marker2,3. Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8+ T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
DNA and RNA sequencing data have been deposited in the European Genome-phenome Archive under accession code EGAS00001003119 and are subject to a controlled Data Access Agreement. These data are available from the corresponding authors to any party able to comply with the associated Data Access Agreement.
Ribas, A. & Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science 359, 1350–1355 (2018).
Galon, J. et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313, 1960–1964 (2006).
Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).
Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Le, D. T. et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Chen, D. S. & Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321–330 (2017).
Andersen, R. S. et al. Dissection of T-cell antigen specificity in human melanoma. Cancer Res. 72, 1642–1650 (2012).
Bobisse, S. et al. Sensitive and frequent identification of high avidity neo-epitope specific CD8 (+) T cells in immunotherapy-naive ovarian cancer. Nat. Commun. 9, 1092 (2018).
Kvistborg, P. et al. Anti-CTLA-4 therapy broadens the melanoma-reactive CD8+T cell response. Sci. Transl. Med. 6, 254ra128 (2014).
Kvistborg, P. et al. TIL therapy broadens the tumor-reactive CD8(+) T cell compartment in melanoma patients. Oncoimmunology 1, 409–418 (2012).
Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).
van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–e442 (2013).
Simoni, Y. et al. Bystander CD8(+) T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018).
Pasetto, A. et al. Tumor- and neoantigen-reactive T-cell receptors can be identified based on their frequency in fresh tumor. Cancer Immunol. Res. 4, 734–743 (2016).
Gros, A. et al. PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J. Clin. Invest. 124, 2246–2259 (2014).
Gros, A. et al. Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients. Nat. Med. 22, 433–438 (2016).
Dahlin, A. M. et al. Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor. Mod. Pathol. 24, 671–682 (2011).
Sato, E. et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA 102, 18538–18543 (2005).
Ye, Q. et al. CD137 accurately identifies and enriches for naturally occurring tumor-reactive T cells in tumor. Clin. Cancer Res. 20, 44–55 (2014).
Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).
Verdegaal, E. M. et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536, 91–95 (2016).
McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271 (2017).
Webb, J. R., Milne, K., Kroeger, D. R. & Nelson, B. H. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol. Oncol. 141, 293–302 (2016).
Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).
Tang, F. et al. RNA-Seq analysis to capture the transcriptome landscape of a single cell. Nat. Protoc. 5, 516–535 (2010).
Bolotin, D. A. et al. MiTCR: software for T-cell receptor sequencing data analysis. Nat. Methods 10, 813–814 (2013).
Linnemann, C. et al. High-throughput identification of antigen-specific TCRs by TCR gene capture. Nat. Med. 19, 1534–1541 (2013).
Ochi, T. et al. Optimization of T-cell reactivity by exploiting TCR chain centricity for the purpose of safe and effective antitumor TCR gene therapy. Cancer Immunol. Res. 3, 1070–1081 (2015).
Kwakkenbos, M. J. et al. Generation of stable monoclonal antibody-producing B cell receptor-positive human memory B cells by genetic programming. Nat. Med. 16, 123–128 (2010).
Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85 (2015).
Gelman, A. et al. Bayesian Data Analysis. (CRC Press, Boca Raton, 2014). .
We thank M. van Zon, N. Bakker, and N. van Rooij for handling of patient material; A. Pfauth for flow cytometric support; S. Reijm for technical assistance; D. Thommen for critical reading of the manuscript; R. van Kerkhoven and M. Nieuwland for support with next generation sequencing; B. Thijssen for helpful discussion on Bayesian analysis; L. Wessels for discussions; the NKI-AVL Core Facility Molecular Pathology & Biobanking for supplying NKI-AVL Biobank material and laboratory support; H. Spits and R. Schotte (AIMM Therapeutics) for sharing reagents for B cell immortalization; K. van de Vijver for histological support; and M. Kranendonk for critical reading of the manuscript and histological support. This work was supported by the Dutch Cancer Society Queen Wilhelmina Award NKI 2013−6122, EU H2020 grant 633592 (APERIM), and the K.G. Jebsen Foundation (T.N.S.), Krebsliga Beider Basel (C.H.), and BC Cancer Foundation (B.H.N.).
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figures 1–10
TCR sequencing data
CMV and EBV epitopes
About this article
Cite this article
Scheper, W., Kelderman, S., Fanchi, L.F. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat Med 25, 89–94 (2019). https://doi.org/10.1038/s41591-018-0266-5
Single‐cell transcriptome analysis revealed the heterogeneity and microenvironment of gastrointestinal stromal tumors
Cancer Science (2021)
PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15
Cellular & Molecular Immunology (2021)
Ag2S nanoparticle-mediated multiple ablations reinvigorates the immune response for enhanced cancer photo-immunotherapy
Advances in identification and selection of personalized neoantigen/T-cell pairs for autologous adoptive T cell therapies
Trends in Cancer (2021)