T-cell tumour exclusion and immunotherapy resistance: a role for CAF targeting


Recent studies have highlighted a major role for cancer-associated fibroblasts (CAFs) in promoting immunotherapy resistance by excluding T cells from tumours. Recently, we showed that CAFs can be effectively targeted by inhibiting the enzyme NOX4; this ‘normalises’ CAFs and overcomes immunotherapy resistance. Here we discuss our study and other strategies for CAF targeting.

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Fig. 1: Schematic showing possible strategies for targeting CAFs and overcoming CAF-mediated T-cell exclusion from tumours.


  1. 1.

    Feig, C., Jones, J. O., Kraman, M., Wells, R. J., Deonarine, A., Chan, D. S. et al. (2013). Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).

    CAS  Article  Google Scholar 

  2. 2.

    Mariathasan, S., Turley, S. J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y. et al. TGFbeta attenuates tumor response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544–548 (2018).

    CAS  Article  Google Scholar 

  3. 3.

    Ford, K., Hanley, C. J., Mellone, M., Szyndralewiez, C., Heitz, F., Wiesel, P. et al. NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell exclusion from tumors. Cancer Res. 80, 1846–1860 (2020).

    CAS  Article  Google Scholar 

  4. 4.

    Hanley, C. J., Mellone, M., Ford, K., Thirdborough, S. M., Mellows, T., Frampton, S. J. et al. Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. J. Natl Cancer Inst. 110, 109–120 (2018).

    CAS  Article  Google Scholar 

  5. 5.

    Elyada, E., Bolisetty, M., Laise, P., Flynn, W. F., Courtois, E. T., Burkhart, R. A. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Disco. 9, 1102–1123 (2019).

    CAS  Article  Google Scholar 

  6. 6.

    Kieffer, Y., Hocine, H. R., Gentric, G., Pelon, F., Bernard, C., Bourachot, B., et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-19-1384 (2020).

  7. 7.

    Hanley, C. J., Waise, S., Parker, R., Maria-Lopez, M.,. Kimbley, L. M., West, J., et al. Spatially discrete signalling niches regulate fibroblast heterogeneity in human lung cancer. Preprint at https://www.biorxiv.org/content/10.1101/2020.06.08.134270v1.full (2020).

  8. 8.

    Dominguez, C. X., Müller, S., Keerthivasan, S., Koeppen, H., Hung, J., Gierke, S. et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Disco. 10, 232–253 (2020).

    CAS  Article  Google Scholar 

  9. 9.

    Sherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H. et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 159, 80–93 (2014).

    CAS  Article  Google Scholar 

  10. 10.

    Rhim, A. D., Oberstein, P. E., Thomas, D. H., Mirek, E. T., Palermo, C. F., Sastra, S. A. et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25, 735–747 (2014).

    CAS  Article  Google Scholar 

  11. 11.

    Chen, I. X., Chauhan, V. P., Posada, J., Ng, M. R., Wu, M. W., Adstamongkonkul, P. et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc. Natl Acad. Sci. USA 116, 4558–4566 (2019).

    CAS  Article  Google Scholar 

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G.T. conceived the paper and C.H contributed to its writing. Both approved the final version.

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Correspondence to Gareth J. Thomas.

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Competing interests

C.J. Hanley and G.J. Thomas are co-inventors on patent WO2019086579.

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The work described in the commentary was funded through Cancer Research UK (grant nos. A203904, A20256 and A27989) and Medical Research Council UK (grant no. MR/P013414/1).

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Hanley, C.J., Thomas, G.J. T-cell tumour exclusion and immunotherapy resistance: a role for CAF targeting. Br J Cancer 123, 1353–1355 (2020). https://doi.org/10.1038/s41416-020-1020-6

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