T-cell diversification reflects antigen selection in the blood of patients on immune checkpoint inhibition and may be exploited as liquid biopsy biomarker

Abstract

Cancer immunotherapy with antibodies targeting immune checkpoints, such as programmed cell death protein 1 (PD-1), shows encouraging results, but reliable biomarkers predicting response to this costly and potentially toxic treatment approach are still lacking. To explore an immune signature predictive for response, we performed liquid biopsy immunoprofiling in 18 cancer patients undergoing PD-1 inhibition before and shortly after initiation of treatment by multicolor flow cytometry and nextgeneration T-and B-cell immunosequencing (TCRß/IGH). Findings were correlated with clinical outcomes. We found almost complete saturation of surface PD-1 on all T-cell subsets after the first dose of the antibody. Both T-and B-cell compartments quantitatively expanded during treatment. These expansions were mainly driven by an increase in the activated T-cell compartments, as well as of na€ ıve B-and plasma cells. Deep immunosequencing revealed a clear diversification pattern of the clonal T-cell space indicative of antigenic selection in 47% of patients, while the remaining patients showed stable repertoires. 43% of the patients with a diversification pattern showed disease control in response to the PD-1 inhibitor. No disease stabilizations were observed without clonal T-cell space diversification. Our data show for the first time a clear impact of PD-1 targeting not only on circulating T-cells, but also on B-lineage cells, shedding light on the complexity of the anti-tumor immune response. Liquid biopsy T-cell next-generation immunosequencing should be prospectively evaluated as part of a composite response prediction biomarker panel in the context of clinical studies.

Characteristics and prognostic significance of profiling the peripheral blood T‐cell receptor repertoire in patients with advanced lung cancer

“…S14). These results confirm that diversity change within 10% reflects stable TCR repertoire diversity …”

“…S13a). A previous study also indicated that peripheral blood CDR3 diversity changes within 10% represent a stable‐diversity status and reflect a poor prognosis . Some low frequency T‐cell clones may only be detected once even in the same sample, which may introduce bias to the analysis.…”

“…Furthermore, tumor tissue is difficult to obtain and dynamically monitor, especially in patients with advanced disease. The use of blood samples is an attractive alternative to overcome these problems . However, before TCR diversity in blood samples can be used to direct disease monitoring and therapy, we must attain a better understanding of the impact of lung cancer on TCR diversity.…”

Tumor Evolution as a Therapeutic Target

“…trace the "evolution" of T lymphocytes in response to tumor evolution itself (136,98,137). Thus, recognition of patterns of tumor progression through multiregion biopsy and liquid biopsies might provide new therapeutic strategies tailored to cancer evolution and tumor-microenvironmental background in individual patients.…”

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…Checkpoint blockade is seen to induce diversification of T cell receptor repertoire [217] , which has been suggested as a biomarker for PD-1 inhibitor disease stabilization [218] . The assessment of TCR repertoire diversity is becoming increasingly accessible [219] .…”