Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in
Jiajia Zhang1,2, Zhicheng Ji3, Justina X Caushi1,2
1The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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.
Insights
Peripheral T-cell dynamics, tracked by T-cell receptor (TCR) sequencing, can predict response to neoadjuvant PD-1 blockade in non-small cell lung cancer (NSCLC). Greater T-cell sharing between tumor and blood indicates better pathologic response to immunotherapy.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Neoadjuvant PD-1 blockade shows promise for resectable non-small cell lung cancer (NSCLC).
- Mechanisms of tumor regression and response biomarkers remain largely unknown.
- Understanding T-cell dynamics is crucial for optimizing immunotherapy.
Purpose of the Study:
- To investigate T-cell receptor (TCR) clonotypic dynamics in peripheral blood as a biomarker for response to neoadjuvant PD-1 blockade in NSCLC.
- To explore the relationship between T-cell repertoire changes and pathologic response.
- To identify immunologic correlates of treatment efficacy.
Main Methods:
- T-cell receptor (TCR) sequencing of paired tumor and peripheral blood samples from NSCLC patients undergoing neoadjuvant PD-1 blockade.
- Analysis of temporal dynamics of T-cell repertoire in tumoral and peripheral compartments.
- Correlation of TCR clonality and repertoire sharing with pathologic response metrics.
Main Results:
- Higher intratumoral TCR clonality correlated with reduced residual tumor post-treatment.
- Tumors with major pathologic response (MPR) exhibited higher TCR clonality and greater peripheral blood sharing.
- Expanded peripheral T-cell clones were enriched in the post-treatment tumor bed of MPR patients.
Conclusions:
- Exchange of T-cell clones between tumor and blood is a key correlate of pathologic response to neoadjuvant immunotherapy.
- The peripheral immune compartment may be an underappreciated source of effective antitumor immunity.
- TCR repertoire analysis offers a potential biomarker for predicting response to PD-1 blockade in NSCLC.
