Abstract
Currently approved inhibitors of the PD-1/PD-L1 pathway represent a major advance for the treatment of lung cancers, yet they are ineffective in a majority of patients due to lack of preexisting T-cell reactivity. Here, we show that a TLR9 agonist delivered by inhalation is able to prime T-cell responses against poorly immunogenic lung tumors and to complement the effects of PD-1 blockade. Inhaled TLR9 agonist causes profound remodeling in tumor-bearing lungs, leading to the formation of tertiary lymphoid structures adjacent to the tumors, CD8+ T-cell infiltration into the tumors, dendritic cell expansion, and antibody production. Inhalation of TLR9 agonist also increased the pool of functional PD-1lowT-bethigh effector CD8+ T cells in tumor-bearing lungs. Effector CD8+ T cells generated by inhaled TLR9 agonist treatment were licensed by PD-1 blockade to become highly functional CTLs, leading to a durable rejection of both lung tumors and tumor lesions outside the lungs. CD4+ T cells activated in response to inhaled TLR9 play a critical role in this process by controlling the proliferation, preventing exhaustion, and guiding the differentiation of optimally functional CTLs. This study characterizes a strategy to apply localized TLR9 stimulation to a tumor type not accessible for direct injection, a strategy that may expand the therapeutic potential of PD-1 blockade in non-small cell lung cancer.Significance: These findings demonstrate that local delivery of a toll-like receptor 9 agonist can change the immune content of an entire organ and enhance the efficacy of immune checkpoint inhibition.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4943/F1.large.jpg Cancer Res; 78(17); 4943-56. ©2018 AACR.
Highlights
Studies in mice have demonstrated that local intratumoral injection of an oligonucleotide containing immunostimulatory CpG motifs (CpG-ODN) signaling through Toll-like receptor-9 (TLR9) can control tumor growth by coordinated activation of both innate and adaptive responses [1]
There are autochthonous lung models that are more reflective of primary lung cancer, this 4T1 model is particular suited to understand whether local administration of a TLR9 agonist through the airways generates, by local stimulation, antitumor responses that can migrate to and control metastases throughout the body
The TLR9 agonist chosen for these studies, SD-101, is a C class CpG-ODN that is capable of inducing high levels of type I IFNs as well as efficient dendritic cell (DC) and B-cell maturation [6]
Summary
Studies in mice have demonstrated that local intratumoral injection of an oligonucleotide containing immunostimulatory CpG motifs (CpG-ODN) signaling through Toll-like receptor-9 (TLR9) can control tumor growth by coordinated activation of both innate and adaptive responses [1]. In phase I/II clinical trials in patients with lymphoma, intratumoral injection of CpG-ODN in combination with low-dose radiotherapy resulted in shrinkage of untreated tumor lesions (abscopal responses), demonstrating that localized stimulation through TLR9 is an effective strategy to www.aacrjournals.org increase systemically active tumor immunity [2]. Systemic administration of TLR9 agonists has generally proven unsuccessful, both in humans [3] and in mouse tumor models [4]. This limits the application of CpG-ODN to tumor types with at least one lesion accessible for repeated injections. A similar approach for delivering a TLR9 agonist to patients with lung cancer appears feasible
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