Editors' ChoiceImmunotherapy

Resisting resistance: Homing in on better immunotherapy responses

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Science Translational Medicine  29 May 2019:
Vol. 11, Issue 494, eaax9556
DOI: 10.1126/scitranslmed.aax9556


In mouse tumor models, the CXCR3-CXCL9 chemokine system mediates sensitivity to PD-1 blockade and could be exploited to enhance responsiveness to checkpoint inhibitors.

The advent of immune checkpoint inhibitors has revolutionized cancer treatment, with the chance of durable, long-term responses even in patients with advanced clinical stages, who previously had a very poor overall prognosis. Despite these advances, the number of patients with such impressive responses is still limited, with a considerable proportion experiencing only small or even lack treatment effects. The reason for this discrepancy is incompletely understood, with the urgent need for the elucidation of underlying mechanisms to augment future treatment strategies.

To unravel supportive mechanisms of anti–programmed cell death–1 (anti–PD-1) cancer treatment, Chow et al. investigated murine transplanted melanoma and colon cancer models previously shown to be responsive to anti–PD-1 treatment. Responses were substantially diminished when the chemokine receptor CXCR3 was missing. In this model, which involved the endogenous generation and trafficking of tumor-specific T cells, this chemokine axis was dispensable for early, baseline T cell infiltration of the tumor but was essential for proliferation and effector function of local, pre-existing CD8+ T cells upon anti–PD-1 treatment. Consistently, fingolimod—a substance that sequesters lymphocytes in the lymph nodes and thus prevents peripheral tissue homing—did not substantially diminish anti–PD-1 treatment effects when administered during anti–PD-1 therapy but did so when given before tumor inoculation. The therapeutic benefits of PD-1 blockade were partially lost in mice lacking the CXCR3 ligand CXCL9 but not CXCL10, indicating a central role for this specific chemokine in anti–PD-1 immunotherapy. Local myeloid dendritic cells produced high amounts of CXCL9 in anti–PD-1-responsive tumors and enhancing expression with epigenetic modulators such as DZNeP and 5-AZA-dC induced responses in an anti–PD-1–resistant breast cancer. Results from these murine tumor experiments were complemented by data from melanoma patients, as drug responders showed more CXCL9 and CXCL10 in the serum than nonresponders within months after initiation of therapy. Despite the fact that there was still a residual antitumor effect of anti–PD-1 treatment in CXCR3 and CXCL9 knockout mice that needs further investigation in other types of cancer models, this chemokine system could be a promising target to overcome checkpoint inhibitor resistance via modification of the tumor microenvironment.

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