Editors' ChoiceCancer

Combination therapy is a game of strategy

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Sci. Signal.  08 Jan 2019:
Vol. 12, Issue 563, eaaw5563
DOI: 10.1126/scisignal.aaw5563

For combination therapy, knowing the “how” and “when” is just as important as knowing the “what.”

Immunotherapy is changing both treatment strategy and survival outlook for patients with cancer, especially those with melanoma. However, its efficacy is limited to a subset of patients and is reduced by existing or acquired drug resistance. Combined inhibition of these resistance pathways can overcome resistance to some extent. However, Zhao et al. found that when it comes to combination therapies, knowing the “when” is just as important as knowing the “what” (see also Puré). In various tumors, signaling by transforming growth factor–β (TGF-β) promotes an immunotolerant microenvironment and resistance to checkpoint inhibitors, a class of immunotherapy that includes anti–programmed cell death 1 (PD-1) and blocks “off-switches” on T cells. One would expect, then, that blocking TGF-β signaling would enhance the efficacy of checkpoint inhibitors. However, TGF-β pathway inhibitors failed to improve the poor efficacy of anti–PD-1 against tumor growth. This failure was because of the effects of TGF-β inhibition in the tumor stroma: TGF-β inhibition increased the proliferation of tumor-associated fibroblasts, which increased the amount of the metalloprotease MMP-9 in the tumor microenvironment. The increase in MMP-9 resulted in more cleavage and, hence, less abundance of PD-L1 (the PD-1 ligand) on the surface of the tumor cells, which reduced the efficacy of anti–PD-1. However, analysis of melanoma samples from treated patients or a mouse model revealed that anti–PD-1 increased the expression of genes associated with TGF-β signaling activation. In the mouse model, delaying the addition of TGF-β inhibitor during continuous anti–PD-1 therapy induced tumor regression and improved the profile of antitumor immune responses. These findings show that, contrary to initial expectations, a sequential rather than simultaneous approach might improve the overall response to anti–PD-1/TGF-β inhibitor combination therapy in patients. These findings also highlight the need to incorporate the tumor microenvironment in cancer therapy studies.

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