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