Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours

Abstract

The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained anti-tumoral activity and prolonged animal survival only when co-expressing C-X-C chemokine receptor type 6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: CXCL16 is expressed in murine pancreatic tumours and affects CXCR6-engineered T cells.
Fig. 2: CXCR6-transduced T cells induce tumour regression.
Fig. 3: CXCR6-transduced T cells are recruited into tumour tissue.
Fig. 4: CXCL16 expressed by human pancreatic cancer cells enhances the cytotoxic activity of engineered T cells.
Fig. 5: CXCL16 is expressed by PDAC specimens and attracts CXCR6-transduced T cells.

Data availability

The main data supporting the results of this study are available within the paper and its Supplementary Information. The raw and analysed datasets generated during this study are too large to be publicly shared, but they are available for research purposes from the corresponding author upon reasonable request. They also contain personal and patient data and are available for research purposes pending completion of adequate paper work ensuring personal data protection and ethical approval. RNA-sequencing data in this study have been published previously and are accessible through the NCBI Gene Expression Omnibus (accession codes GSE84133 and GSE122960), NCBI BioProject database (accession code PRJEB31843), Genome Sequence Archive (accession number CRA001160) and Synapse (https://www.synapse.org/#!Synapse:syn21041850/files/).

References

  1. 1.

    Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Kobold, S. et al. Immunotherapy in tumors. Dtsch. Ärztebl. Int. 112, 809–815 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. 3.

    Sheridan, C. First approval in sight for Novartis’ CAR-T therapy after panel vote. Nat. Biotechnol. 35, 691–693 (2017).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)—specific chimeric antigen recpetor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Adusumilli, P. S. et al. Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Sci. Transl. Med. 6, 261ra151 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaaa0984 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Tchou, J. et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol. Res. 5, 1152–1161 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Akbay, E. A. et al. Interleukin-17A promotes lung tumor progression through neutrophil attraction to tumor sites and mediating resistance to PD-1 blockade. J. Thorac. Oncol. 12, 1268–1279 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Bauer, C. A. et al. Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J. Clin. Invest. 124, 2425–2440 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Linke, B. et al. CXCL16/CXCR6-mediated adhesion of human peripheral blood mononuclear cells to inflamed endothelium. Cytokine 122, 154081 (2019).

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Polański, K. et al. BBKNN: fast batch alignment of single cell transcriptomes. Bioinformatics 36, 964–965 (2020).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Tokarew, N., Ogonek, J., Endres, S., von Bergwelt-Baildon, M. & Kobold, S.Teaching an old dog new tricks: next-generation CAR T cells. Br. J. Cancer 120, 26–37 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Grosser, R., Cherkassky, L., Chintala, N. & Adusumilli, P. S. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 36, 471–482 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Rapp, M. et al. C-C chemokine receptor type-4 transduction of T cells enhances interaction with dendritic cells, tumor infiltration and therapeutic efficacy of adoptive T cell transfer. OncoImmunology 5, e1105428 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  16. 16.

    Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18.

    Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Garetto, S. et al. Tailored chemokine receptor modification improves homing of adoptive therapy T cells in a spontaneous tumor model. Oncotarget 7, 43010–43026 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Siddiqui, I., Erreni, M., van Brakel, M., Debets, R. & Allavena, P. Enhanced recruitment of genetically modified CX3CR1-positive human T cells into Fractalkine/CX3CL1 expressing tumors: importance of the chemokine gradient. J. Immunother. Cancer 4, 21 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Muller, N. et al. Engineering NK cells modified with an EGFRvIII-specific chimeric antigen receptor to overexpress CXCR4 improves immunotherapy of CXCL12/SDF-1α-secreting glioblastoma. J. Immunother. 38, 197–210 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Moon, E. K. et al. Expression of a functional CCR2 receptor enhances tumor localization and tumor eradication by retargeted human T cells expressing a mesothelin-specific chimeric antibody receptor. Clin. Cancer Res. 17, 4719–4730 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Peng, W. et al. Transduction of tumor-specific T cells with CXCR2 chemokine receptor improves migration to tumor and antitumor immune responses. Clin. Cancer Res. 16, 5458–5468 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Shimaoka, T. et al. Cell surface-anchored SR-PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6-expressing cells. J. Leukoc. Biol. 75, 267–274 (2004).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Kobold, S. et al. Impact of a new fusion receptor on PD-1-mediated immunosuppression in adoptive T cell therapy. J. Natl Cancer Inst. 107, djv146 (2015).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Li, K. et al. Impact of chemokine receptor CXCR3 on tumor-infiltrating lymphocyte recruitment associated with favorable prognosis in advanced gastric cancer. Int. J. Clin. Exp. Pathol. 8, 14725–14732 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Madissoon, E. et al. scRNA-seq assessment of the human lung, spleen, and esophagus tissue stability after cold preservation. Genome Biol. 21, 1 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Deng, L., Chen, N., Li, Y., Zheng, H. & Lei, Q. CXCR6/CXCL16 functions as a regulator in metastasis and progression of cancer. Biochim. Biophys. Acta 1806, 42–49 (2010).

    CAS  PubMed  Google Scholar 

  29. 29.

    Wente, M. N. et al. Expression and potential function of the CXC chemokine CXCL16 in pancreatic ductal adenocarcinoma. Int. J. Oncol. 33, 297–308 (2008).

    CAS  PubMed  Google Scholar 

  30. 30.

    Heydtmann, M. et al. CXC chemokine ligand 16 promotes integrin-mediated adhesion of liver-infiltrating lymphocytes to cholangiocytes and hepatocytes within the inflamed human liver. J. Immunol. 174, 1055–1062 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Rataj, F. et al. PD1–CD28 fusion protein enables CD4+ T cell help for adoptive T cell therapy in models of pancreatic cancer and non-Hodgkin lymphoma. Front. Immunol. https://doi.org/10.3389/fimmu.2018.01955 (2018).

  32. 32.

    Sato, T. et al. Role for CXCR6 in recruitment of activated CD8+ lymphocytes to inflamed liver. J. Immunol. 174, 277–283 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Unutmaz, D. et al. The primate lentiviral receptor Bonzo/STRL33 is coordinately regulated with CCR5 and its expression pattern is conserved between human and mouse. J. Immunol. 165, 3284–3292 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Karches, C. H. et al. Bispecific antibodies enable synthetic agonistic receptor-transduced T cells for tumor immunotherapy. Clin. Cancer Res. 25, 5890–5900 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Paulos, C. M. et al. Microbial translocation augments the function of adoptively transferred self/tumor-specific CD8+ T cells via TLR4 signaling. J. Clin. Invest. 117, 2197–2204 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Kobold, S. et al. Selective bispecific T cell recruiting antibody and antitumor activity of adoptive T cell transfer. J. Natl Cancer Inst. 107, 364 (2015).

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Chinnasamy, D. et al. Local delivery of interleukin-12 using T cells targeting VEGF receptor-2 eradicates multiple vascularized tumors in mice. Clin. Cancer Res. 18, 1672–1683 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Jin, L. et al. CXCR1- or CXCR2-modified CAR T cells co-opt IL-8 for maximal antitumor efficacy in solid tumors. Nat. Commun. 10, 4016 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Schizas, D. et al. Immunotherapy for pancreatic cancer: a 2020 update. Cancer Treat. Rev. 86, 102016 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Hartmann, N. et al. Prevailing role of contact guidance in intrastromal T-cell trapping in human pancreatic cancer. Clin. Cancer Res. 20, 3422–3433 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Kocher, H. M. et al. Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. Nat. Commun. 11, 4841 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Alvarez, R. et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br. J. Cancer 109, 926–933 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Lo, A. et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res. 75, 2800–2810 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Matloubian, M., David, A., Engel, S., Ryan, J. E. & Cyster, J. G. A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo. Nat. Immunol. 1, 298–304 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Linke, B. et al. CXCL16/CXCR6-mediated adhesion of human peripheral blood mononuclear cells to inflamed endothelium. Cytokine 122, 154081 (2019).

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    Collado, A. et al. Functional role of endothelial CXCL16/CXCR6–platelet–leucocyte axis in angiotensin II-associated metabolic disorders. Cardiovasc. Res. 114, 1764–1775 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Sackstein, R., Schatton, T. & Barthel, S. R. T-lymphocyte homing: an underappreciated yet critical hurdle for successful cancer immunotherapy. Lab. Invest. 97, 669–697 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Agostini, C. et al. Role for CXCR6 and its ligand CXCL16 in the pathogenesis of T-cell alveolitis in sarcoidosis. Am. J. Respir. Crit. Care Med. 172, 1290–1298 (2005).

    PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Oldham, K. A. et al. T lymphocyte recruitment into renal cell carcinoma tissue: a role for chemokine receptors CXCR3, CXCR6, CCR5, and CCR6. Eur. Urol. 61, 385–394 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    La Porta, C. A. CXCR6: the role of environment in tumor progression. Challenges for therapy. Stem Cell Rev. 8, 1282–1285 (2012).

    Article  CAS  Google Scholar 

  52. 52.

    Allaoui, R. et al. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Nat. Commun. 7, 13050 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Chalabi-Dchar, M. et al. Loss of somatostatin receptor subtype 2 promotes growth of KRAS-induced pancreatic tumors in mice by activating PI3K signaling and overexpression of CXCL16. Gastroenterology 148, 1452–1465 (2015).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Hu, W., Liu, Y., Zhou, W., Si, L. & Ren, L. CXCL16 and CXCR6 are coexpressed in human lung cancer in vivo and mediate the invasion of lung cancer cell lines in vitro. PLoS ONE 9, e99056 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Slaga, D. et al. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3. Sci. Transl. Med. 10, eaat5775 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  57. 57.

    Morello, A., Sadelain, M. & Adusumilli, P. S. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov 6, 133–146 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Beatty, G. L. et al. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155, 29–32 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Fujita, K. et al. Prolonged disease-free period in patients with advanced epithelial ovarian cancer after adoptive transfer of tumor-infiltrating lymphocytes. Clin. Cancer Res. 1, 501–507 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Hall, M. et al. Expansion of tumor-infiltrating lymphocytes (TIL) from human pancreatic tumors. J. Immunother. Cancer 4, 61 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Nanki, T. et al. Pathogenic role of the CXCL16–CXCR6 pathway in rheumatoid arthritis. Arthritis Rheum. 52, 3004–3014 (2005).

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Akce, M., Zaidi, M. Y., Waller, E. K., El-Rayes, B. F. & Lesinski, G. B. The potential of CAR T cell therapy in pancreatic cancer. Front. Immunol. 9, 2166 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Jacobs, C. et al. An ISCOM vaccine combined with a TLR9 agonist breaks immune evasion mediated by regulatory T cells in an orthotopic model of pancreatic carcinoma. Int. J. Cancer 128, 897–907 (2011).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Anz, D. et al. Suppression of intratumoral CCL22 by type I interferon inhibits migration of regulatory T cells and blocks cancer progression. Cancer Res. 75, 4483–4493 (2015).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Ghani, K. et al. Efficient human hematopoietic cell transduction using RD114- and GALV-pseudotyped retroviral vectors produced in suspension and serum-free media. Hum. Gene Ther. 20, 966–974 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Metzger, P. et al. Immunostimulatory RNA leads to functional reprogramming of myeloid-derived suppressor cells in pancreatic cancer. J. Immunother. Cancer 7, 288 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Larimer, B. M. et al. Granzyme B PET imaging as a predictive biomarker of immunotherapy response. Cancer Res. 77, 2318–2327 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Larimer, B. M. et al. The effectiveness of checkpoint inhibitor combinations and administration timing can be measured by granzyme B pet imaging. Clin. Cancer Res. 25, 1196–1205 (2019).

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Rühland, S. et al. Quantification of in vitro mesenchymal stem cell invasion into tumor spheroids using selective plane illumination microscopy. J. Biomed. Opt. 20, 040501 (2015).

    PubMed  Article  Google Scholar 

  70. 70.

    Schmohl, K. A. et al. Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3. Endocr. Relat. Cancer 22, 941–952 (2015).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Renz, B. W. et al. β2 adrenergic–neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell. 33, 75–90.e7 (2018).

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Renz, B. W. et al. Cholinergic signaling via muscarinic receptors directly and indirectly suppresses pancreatic tumorigenesis and cancer stemness. Cancer Discov. 8, 1458–1473 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Ruess, D. A. et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat. Med. 24, 954–960 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Reichert, M. et al. Isolation, culture and genetic manipulation of mouse pancreatic ductal cells. Nat. Protoc. 8, 1354–1365 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Halama, N. et al. Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients. Cancer Cell 29, 587–601 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Halama, N. et al. Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 71, 5670–5677 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Goldman, M. et al. Visualizing and interpreting cancer genomics data via the Xena platform. Nat. Biotechnol. 38, 675–678 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Wolf, F. A., Angerer, P. & Theis, F. J. SCANPY: large-scale single-cell gene expression data analysis. Genome Biol. 19, 15–15 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Travaglini, K. J. et al. A molecular cell atlas of the human lung from single-cell RNA sequencing. Nature 587, 619–625 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Reyfman, P. A. et al. Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 199, 1517–1536 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Peng, J. et al. Single-cell RNA-seq highlights intra-tumoral heterogeneity and malignant progression in pancreatic ductal adenocarcinoma. Cell Res. 29, 725–738 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Baron, M. et al. A single-cell transcriptomic map of the human and mouse pancreas reveals inter- and intra-cell population structure. Cell Syst. 3, 346–360 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Lun, A. T. L., Bach, K. & Marioni, J. C. Pooling across cells to normalize single-cell RNA sequencing data with many zero counts. Genome Biol. 17, 75 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  84. 84.

    Zheng, G. X. Y. et al. Massively parallel digital transcriptional profiling of single cells. Nat. Commun. 8, 14049 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    McInnes L., Healy J. & Melville J. UMAP: uniform manifold approximation and projection for dimension reduction. Preprint at https://arxiv.org/abs/1802.03426 (2020).

  86. 86.

    Muus, C. et al. Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics. Nat. Med. 27, 546–559 (2021).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the Wilhelm Sander-Stiftung (grant number 2014.018.1 to S.E. and S. Kobold), international doctoral program ‘i-Target: immunotargeting of cancer’ (funded by the Elite Network of Bavaria; to S. Kobold and S.E.), Melanoma Research Alliance (grant number N269626 to S.E. and grant number 409510 to S. Kobold), Marie Sklodowska-Curie Training Network for the Immunotherapy of Cancer (IMMUTRAIN) (funded by the Horizon 2020 programme of the European Union; to S.E. and S. Kobold), Marie Sklodowska-Curie Training Network for Optimizing Adoptive T Cell Therapy of Cancer (funded by the Horizon 2020 programme of the European Union; grant 955575 to S. Kobold), Else Kröner-Fresenius-Stiftung (to S. Kobold), German Cancer Aid (to S. Kobold), Ernst Jung Stiftung (to S. Kobold), Institutional Strategy LMUexcellent of LMU Munich (within the framework of the German Excellence Initiative; to S.E. and S. Kobold), Bundesministerium für Bildung und Forschung (to S.E. and S. Kobold), European Research Council (Starting Grant 756017 to S. Kobold), Deutsche Forschungsgemeinschaft (DFG; to S. Kobold), Fritz-Bender Foundation (to S. Kobold), José Carreras Foundation (to S. Kobold) and Hector Foundation (to S. Kobold). R.T.A.M. is supported by the DFG (INST409/97-1 FUGG), SFB1123/Z1 and ERA-CVD (AtheroInside). Z.D. was supported by an AGA-Moti L. & Kamla Rustgi International Travel Award. M. Reichert was supported by German Cancer Aid (Max Eder Program; Deutsche Krebshilfe 111273) and the DFG (SFB1321 (Modeling and Targeting Pancreatic Cancer) and RE 3723/4-1). E.D. was supported by a grant from INSERM (HTE: chemotaxis in cancer). M.T. is funded by the Volkswagen Foundation (project OntoTime). C.M. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement number 866411). M. Schnurr was supported by the DFG (SFB1321 (Modeling and Targeting Pancreatic Cancer); project number 329628492). We acknowledge the iFlow Core Facility of the University Hospital of Munich for assistance with the generation of flow cytometry data. Image processing using the Imaris 7.6.5 software was performed at the Core Facility for Bioimaging of the Biomedical Center of the Ludwig-Maximilians-Universität München.

Author information

Affiliations

Authors

Contributions

S.L., V.B., S.S., J.O., B.L.C., Z.D., F.R., K.D., J.L., C.H.K., C. Heise, M.K., B.M.L., S.G., M. Rapp, A.N., A.G., S. Kruger, N.T., P.M., C. Hoerth, M.-R.B., D.D., A.O., R.G., M. Seifert, S.J., Ö.U., L.V., M.T., T.T., T.H., T.B., D.H., R.T.A.M., K.-P.J., M.J., D.L., S. Ruehland, M.D.P., J.N.P., M.T., S.O., C.M., E.T., E.D., M.H., A.R., S. Rothenfusser, P.D., L.M.K. and M. Schnurr performed or assisted with the experiments, analysed the data and supported the project. S. Kobold and S.E. supervised the project and acquired the funding. S. Kobold, S.L., V.B., S.S., J.O., B.L.C., M. Subklewe, A.S.L., N.H., M. Reichert and T.R.M. designed the experiments. S. Kobold and S.L. wrote the manuscript. All authors critically read and approved the final manuscript.

Corresponding author

Correspondence to Sebastian Kobold.

Ethics declarations

Competing interests

Parts of this work have been performed for the doctoral theses of S.L., V.B., S.S., K.D. and J.L. at the Ludwig-Maximilians-Universität München. M. Rapp, S.G., S.E. and S. Kobold are inventors on a patent application related to this work (PCT/EP2016/074644), filed by the Ludwig-Maximilians-Universität München. S.E. and S. Kobold received research support from TCR2 Therapeutics and Arcus Biosciences for work on T cell therapies unrelated to the present manuscript. The remaining authors declare no competing interests.

Additional information

Peer review information Nature Biomedical Engineering thanks Eduard Ryschich, Prasad Adusumilli and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

Supplementary Figs. 1–8 and Tables 1 and 2.

Reporting Summary

Peer Review File

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Lesch, S., Blumenberg, V., Stoiber, S. et al. T cells armed with C-X-C chemokine receptor type 6 enhance adoptive cell therapy for pancreatic tumours. Nat Biomed Eng (2021). https://doi.org/10.1038/s41551-021-00737-6

Download citation

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing