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Proc Natl Acad Sci U S A. 2018 Jul 17;115(29):E6836-E6844. doi: 10.1073/pnas.1803281115. Epub 2018 Jul 2.

Induction of oligoclonal CD8 T cell responses against pulmonary metastatic cancer by a phospholipid-conjugated TLR7 agonist.

Author information

1
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0695.
2
Graduate School of Tokyo Medical and Dental University, 113-8519, Tokyo, Japan.
3
Repertoire Genesis Inc., Ibaraki-shi, 567-0085 Osaka, Japan.
4
Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0695; dcarson@ucsd.edu thayashi@ucsd.edu.

Abstract

Recent advances in cancer immunotherapy have improved patient survival. However, only a minority of patients with pulmonary metastatic disease respond to treatment with checkpoint inhibitors. As an alternate approach, we have tested the ability of systemically administered 1V270, a toll-like receptor 7 (TLR7) agonist conjugated to a phospholipid, to inhibit lung metastases in two variant murine 4T1 breast cancer models, as well as in B16 melanoma, and Lewis lung carcinoma models. In the 4T1 breast cancer models, 1V270 therapy inhibited lung metastases if given up to a week after primary tumor initiation. The treatment protocol was facilitated by the minimal toxic effects exerted by the phospholipid TLR7 agonist compared with the unconjugated agonist. 1V270 exhibited a wide therapeutic window and minimal off-target receptor binding. The 1V270 therapy inhibited colonization by tumor cells in the lungs in an NK cell dependent manner. Additional experiments revealed that single administration of 1V270 led to tumor-specific CD8+ cell-dependent adaptive immune responses that suppressed late-stage metastatic tumor growth in the lungs. T cell receptor (TCR) repertoire analyses showed that 1V270 therapy induced oligoclonal T cells in the lungs and mediastinal lymph nodes. Different animals displayed commonly shared TCR clones following 1V270 therapy. Intranasal administration of 1V270 also suppressed lung metastasis and induced tumor-specific adaptive immune responses. These results indicate that systemic 1V270 therapy can induce tumor-specific cytotoxic T cell responses to pulmonary metastatic cancers and that TCR repertoire analyses can be used to monitor, and to predict, the response to therapy.

KEYWORDS:

T cell receptor repertoire analysis; cancer immunotherapy; lung metastasis; toll like receptor 7 agonist

PMID:
29967183
PMCID:
PMC6055176
[Available on 2019-01-17]
DOI:
10.1073/pnas.1803281115
[Indexed for MEDLINE]
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