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AMD3100/Plerixafor overcomes immune inhibition by the CXCL12–KRT19 coating on pancreatic and colorectal cancer cells

Summary

A recent Phase 1 clinical study of the immunological effects of inhibiting the chemokine receptor, CXCR4, in patients with pancreatic ductal adenocarcinoma or colorectal cancer suggests that stimulation of CXCR4 on immune cells suppresses the intratumoural immune reaction. Here, we discuss how CXCR4 mediates this response, and how cancer cells elicit it.

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Fig. 1: Blocking CXCR4 with AMD3100 allows T cell killing of CXCL12-coated cancer cells.

References

  1. Joyce, J. A. & Fearon, D. T. T cell exclusion, immune privilege, and the tumor microenvironment. Science 348, 74–80 (2015).

    Article  CAS  Google Scholar 

  2. Biasci, D., Smoragiewicz, M., Connell, C. M., Wang, Z., Gao, Y., Thaventhiran, J. E. D. et al. CXCR4 inhibition in human pancreatic and colorectal cancers induces an integrated immune response. Proc. Natl Acad. Sci. USA 117, 28960–28970 (2020).

    Article  CAS  Google Scholar 

  3. Feig, C., Jones, J. O., Kraman, M., Wells, R. J., Deonarine, A., Chan, D. S. et al. 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).

    Article  CAS  Google Scholar 

  4. Wang, Z., Yan, R., Li, J., Gao, Y., Moresco, P., Yao, M. et al. Pancreatic cancer cells assemble a CXCL12-keratin 19 coating to resist immunotherapy. Preprint at bioRxiv https://doi.org/10.1101/776419 (2020).

  5. Chow, M. T., Ozga, A. J., Servis, R. L., Frederick, D. T., Lo, J. A., Fisher, D. E. et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity 50, 1498–1512 (2019).

  6. McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).

    Article  CAS  Google Scholar 

  7. Scott, A. C., Dündar, F., Zumbo, P., Chandran, S. S., Klebanoff, C. A., Shakiba, M. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019).

    Article  CAS  Google Scholar 

  8. Lutz, E. R., Wu, A. A., Bigelow, E., Sharma, R., Mo, G., Soares, K. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation. Cancer Immunol. Res. 2, 616–631 (2014).

    Article  CAS  Google Scholar 

  9. 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).

    Article  CAS  Google Scholar 

  10. Kasashima, H., Duran, A., Martinez-Ordoñez, A., Nakanishi, Y., Kinoshita, H., Linares, J. F. et al. Stromal SOX2 upregulation promotes tumorigenesis through the generation of a SFRP1/2-expressing cancer-associated fibroblast population. Dev. Cell 56, S1534–S5807 (2020).

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Acknowledgements

The authors would like to acknowledge the contribution of Jordan A. Pearson who created Fig. 1.

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DTF contributed to the conception of the work and drafted the manuscript. KD contributed to the writing of the paper. Both authors approved the final version.

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Correspondence to Douglas T. Fearon.

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Fearon, D.T., Janowitz, T. AMD3100/Plerixafor overcomes immune inhibition by the CXCL12–KRT19 coating on pancreatic and colorectal cancer cells. Br J Cancer 125, 149–151 (2021). https://doi.org/10.1038/s41416-021-01315-y

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