Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells
Contributed by Robert L. Coffman, September 30, 2016 (sent for review May 31, 2016; reviewed by Wolf Fridman and Miriam Merad)
Significance
Recent data suggest that patients harboring immunologically incompetent tumors fail to respond to programmed death 1 (PD-1) blockade. We have developed a mouse tumor model that mimics resistance found in human tumors, and we show that intratumoral injections of a high IFN-inducing CpG oligonucleotide, SD-101, can rapidly lead to durable rejection of anti–PD-1 nonresponder tumors and generate systemic immunity to untreated distant-site tumors. The change in tumor microenvironment caused by SD-101 leads to rapid T-cell infiltration and generation of multifunctional CD8+ T cells. These studies provide significant insights into the synergy between PD-1 blockade and local TLR9 activation and provide the experimental support for clinical studies of combination therapy with PD-1 blockade and intratumoral SD-101.
Abstract
Despite the impressive rates of clinical response to programmed death 1 (PD-1) blockade in multiple cancers, the majority of patients still fail to respond to this therapy. The CT26 tumor in mice showed similar heterogeneity, with most tumors unaffected by anti–PD-1. As in humans, response of CT26 to anti–PD-1 correlated with increased T- and B-cell infiltration and IFN expression. We show that intratumoral injection of a highly interferogenic TLR9 agonist, SD-101, in anti–PD-1 nonresponders led to a complete, durable rejection of essentially all injected tumors and a majority of uninjected, distant-site tumors. Therapeutic efficacy of the combination was also observed with the TSA mammary adenocarcinoma and MCA38 colon carcinoma tumor models that show little response to PD-1 blockade alone. Intratumoral SD-101 substantially increased leukocyte infiltration and IFN-regulated gene expression, and its activity was dependent on CD8+ T cells and type I IFN signaling. Anti–PD-1 plus intratumoral SD-101 promoted infiltration of activated, proliferating CD8+ T cells and led to a synergistic increase in total and tumor antigen-specific CD8+ T cells expressing both IFN-γ and TNF-α. Additionally, PD-1 blockade could alter the CpG-mediated differentiation of tumor-specific CD8+ T cells into CD127lowKLRG1high short-lived effector cells, preferentially expanding the CD127highKLRG1low long-lived memory precursors. Tumor control and intratumoral T-cell proliferation in response to the combined treatment is independent of T-cell trafficking from secondary lymphoid organs. These findings suggest that a CpG oligonucleotide given intratumorally may increase the response of cancer patients to PD-1 blockade, increasing the quantity and the quality of tumor-specific CD8+ T cells.
Acknowledgments
We thank the team at Murigenics for assistance with animal work and thank our colleagues at Dynavax for critical reading of the manuscript.
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Freely available online through the PNAS open access option.
Submission history
Published online: October 31, 2016
Published in issue: November 15, 2016
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Acknowledgments
We thank the team at Murigenics for assistance with animal work and thank our colleagues at Dynavax for critical reading of the manuscript.
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Competing Interests
Conflict of interest statement: The authors are present or former employees of Dynavax Technologies, which supported this work and is conducting clinical trials of SD-101 for the treatment of lymphoma and melanoma.
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Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8+ T cells, Proc. Natl. Acad. Sci. U.S.A.
113 (46) E7240-E7249,
https://doi.org/10.1073/pnas.1608555113
(2016).
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