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 Journal Article
| Authors: | Zhang, J.; Ji, Z.; Caushi, J. X.; El Asmar, M.; Anagnostou, V.; Cottrell, T. R.; Chan, H. Y.; Suri, P.; Guo, H.; Merghoub, T.; Chaft, J. E.; Reuss, J. E.; Tam, A. J.; Blosser, R. L.; Abu-Akeel, M.; Sidhom, J. W.; Zhao, N.; Ha, J. S.; Jones, D. R.; Marrone, K. A.; Naidoo, J.; Gabrielson, E.; Taube, J. M.; Velculescu, V. E.; Brahmer, J. R.; Housseau, F.; Hellmann, M. D.; Forde, P. M.; Pardoll, D. M.; Ji, H.; Smith, K. N. |
| Article Title: | 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 |
| 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 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. |
| Keywords: | biomarkers; tumor; therapy; immune checkpoint blockade |
| Journal Title: | Clinical Cancer Research |
| Volume: | 26 |
| Issue: | 6 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2020-03-15 |
| Start Page: | 1327 |
| End Page: | 1337 |
| Language: | English |
| ACCESSION: | WOS:000522838400016 |
| DOI: | 10.1158/1078-0432.Ccr-19-2931 |
| PROVIDER: | wos |
| PMCID: | PMC7073288 |
| PUBMED: | 31754049 |
| Notes: | Article -- Source: Wos |
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