Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non–Small Cell Lung Cancer
Year: 2019
Type: article
Abstract: 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 a molecular 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 patients with MPR 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. See related commentary by Henick, p. 1205
Source: Clinical Cancer Research
Authors: Jiajia Zhang, Zhicheng Ji, Justina X. Caushi, Margueritta El Asmar, Valsamo Anagnostou, Tricia R. Cottrell, Hok Yee Chan, Prerna Suri, Haidan Guo, Taha Merghoub, Jamie E. Chaft, Joshua E. Reuss, Ada J. Tam, Richard L. Blosser, Mohsen Abu-Akeel, John-William Sidhom, Ni Zhao, Jinny S. Ha, David R. Jones, Kristen A. Marrone, Jarushka Naidoo, Edward Gabrielson, Janis M. Taube, Victor E. Velculescu, Julie R. Brahmer, Franck Housseau, Matthew D. Hellmann, Patrick M. Forde, Drew M. Pardoll, Hongkai Ji, Kellie N. Smith
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: V Foundation for Cancer Research, LUNGevity Foundation, Commonwealth Foundation, International Association for the Study of Lung Cancer, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, American College of Radiology Imaging Network, Ludwig Institute for Cancer Research, Parker Institute for Cancer Immunotherapy, Mark Foundation For Cancer Research, Bloomberg Philanthropies, Swim Across America, National Institutes of Health, Stand Up To Cancer, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1387152882, G1663198200, G1884771441, G2205775429, G2226435482, G2288103773, G2404915759, G2491929434, G2665966410, G2695170217, G2818238373, G3015188539, G3169672230, G3479938378, G3549828030, G4102770861, G502731794, G5520316217, G5528104311, G581634963, G5944639382, G6403603385, G6995731259, G7085050081, G7200864337, G7486208442, G7590859546, Cellular and Molecular Medicine, G8439631040, G8510443486, BRMS1-mediated suppression of metastases in p53 mutant lung adenocarcinoma, G9000003249, G9000045725, G9000064454, G9000067759, G9000110692, G9000116656, G9000135923, G9000273400, G9000283243, G9000293433, G9000314181, G9000340775, G9000350068, Cancer Center Support Grant, G986994938
OpenAlex ID: W2991240940