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Immunotherapy

A triple blow for cancer

Nature Reviews Cancer volume 15, page 259 (2015)Cite this article

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Although individual immune checkpoint inhibitors have shown promise as cancer immunotherapies, recent data suggest that greater success will be achieved by combining these inhibitors with each other and possibly with other therapies, such as radiation. Reporting in Nature, Minn and colleagues show that combining antibodies that target the programmed cell death protein 1 (PD1) ligand 1 (PDL1)-mediated and cytotoxic T lymphocyte antigen 4 (CTLA4)-mediated immune checkpoints with radiation promotes effective antitumour immunity through distinct, non-redundant mechanisms.

To understand this resistance, the authors moved to the B6-F10 melanoma mouse model, in which a similar response rate to the radiation plus CTLA4-blocking treatment was observed. Complete responses to therapy were CD8+ T cell dependent, and the best predictor of resistance was the failure to increase the ratio of CD8+CD44+ T cells to regulatory T (TReg) cells (CD8/TReg ratio) within the tumour-infiltrating lymphocyte (TIL) population. The CD8/TReg ratio did not increase in resistant tumours despite a reduction in the number of TReg cells (which was similar to that observed in sensitive tumours) because CD8+ T cells failed to accumulate. This defect in CD8+ T cell accumulation in resistant tumours was due to the increased expression of PDL1 on melanoma cells. A comparable increase in PDL1 expression was observed on resistant breast cancer cells and on resistant tumour cells from patients with metastatic multiple melanoma in the clinical trial.

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References

  1. Twyman-Saint Victor, C. et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature http://dx.doi.org/10.1038/nature14292 (2015)

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  1. Chief Editor, Nature Reviews Immunology,

    Olive Leavy

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  1. Olive Leavy
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Leavy, O. A triple blow for cancer. Nat Rev Cancer 15, 259 (2015). https://doi.org/10.1038/nrc3946

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