期刊
CLINICAL CANCER RESEARCH
卷 26, 期 6, 页码 1327-1337出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-2931
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资金
- Lung Cancer Foundation of America
- International Association for the Study of Lung Cancer Foundation
- National Human Genome Research Institute of the NIH [R01 HG009518]
- NIH [R01 CA20389101A1, CA121113, CA180950, T32 CA193145]
- SU2C/AACR [SU2C-AACR-DT1012]
- Mark Foundation for Cancer Research
- Eastern Cooperative Oncology Group-American College of Radiology Imaging Network
- V Foundation
- LUNGevity Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Commonwealth Foundation
- NCI [R01 CA142779]
- Bloomberg-Kimmel Institute for Cancer Immunotherapy
- Bloomberg Philanthropies
- NIH Cancer Center Support Grant [P30 CA008748, P30 CA008747]
- NIH/NCI [R01 CA056821]
- Swim Across America
- Ludwig Institute for Cancer Research
- Parker Institute for Cancer Immunotherapy
- Virginia B. Squiers Foundation
Purpose: Neoadjuvant PD-1 blockade is a promising treatment for resectable non-small cell lung cancer (NSCLC), yet immunologic mechanisms contributing to tumor regression and biomarkers of response are unknown. Using paired tumor/blood samples from a phase II clinical trial (NCT02259621), we explored whether the peripheral T-cell clonotypic dynamics can serve as a biomarker for response to neoadjuvant PD-1 blockade. Experimental Design: T-cell receptor (TCR) sequencing was performed on serial peripheral blood, tumor, and normal lung samples from resectable NSCLC patients treated with neoadjuvant PD-1 blockade. We explored the temporal dynamics of the T-cell repertoire in the peripheral and tumoral compartments in response to neoadjuvant PD-1 blockade by using the TCR as amolecular barcode. Results: Higher intratumoral TCR clonality was associated with reduced percent residual tumor at the time of surgery, and the TCR repertoire of tumors with major pathologic response (MPR; <10% residual tumor after neoadjuvant therapy) had a higher clonality and greater sharing of tumor-infiltrating clonotypes with the peripheral blood relative to tumors without MPR. Additionally, the posttreatment tumor bed of patientswithMPR was enriched with T-cell clones that had peripherally expanded between weeks 2 and 4 after anti-PD-1 initiation and the intratumoral space occupied by these clonotypes was inversely correlated with percent residual tumor. Conclusions: Our study suggests that exchange of T-cell clones between tumor and blood represents a key correlate of pathologic response to neoadjuvant immunotherapy and shows that the periphery may be a previously underappreciated originating compartment for effective antitumor immunity.
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