Intratumoral injection of a CpG oligonucleotide reverts resistance to PD-1 blockade by expanding multifunctional CD8⁺ T cells

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 46; pp. E7240 - E7249
• Main Authors: Wang, Shu, Campos, Jose, Gallotta, Marilena, Gong, Mei, Crain, Chad, Naik, Edwina, Coffman, Robert L., Guiducci, Cristiana
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.11.2016
• Series: PNAS Plus
• Subjects: Biological Sciences; Cancer therapies; Combined treatment; Gene expression; Heterogeneity; Immunology and Inflammation; Infiltration; Injection; Interferon; Oncology; PNAS Plus; Rodents; T cell receptors; Tumors; PD-1 blockade; TLR9 agonist; multifunctional CD8; T cells; multifunctional CD8+ T cells
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1608555113

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.