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

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. MarroneJarushka 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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1327-1337
Number of pages11
JournalClinical Cancer Research
Issue number6
StatePublished - Mar 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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