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Translational Therapeutics

Persistence and enrichment of dominant T cell clonotypes in expanded tumor-infiltrating lymphocytes of breast cancer

Abstract

Background

Adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) has shown promising results in cancer treatment, including breast cancer. However, clonal dynamics and clinical significance of TIL expansion ex vivo remain poorly understood.

Methods

We investigated T cell receptor (TCR) repertoire changes in expanded TILs from 19 patients with breast cancer. We compared TCR repertoire of TILs at different stages of expansion, including initial (2W TILs) and rapid expansion (REP TILs), and their overlap with formalin fixed paraffin embedded (FFPE) and peripheral blood. Additionally, we examined differences in TCR repertoire between CD4+ and CD8+ REP TILs.

Results

In descending order of proportion, average of 60% of the top 10% clonotypes of FFPE was retained in 2W TIL (60% in TRB, 64.7% in TRA). Among the overlapped clonotypes between 2W TILs and REP TILs, 69.9% was placed in top 30% of 2W TIL. The proportion of clonotypes in 2W TIL and REP TIL showed a significant positive correlation. CD4+ and CD8+ T cells show similar results in diversity and CDR3 length.

Conclusions

Our study traces the changes in TILs repertoire from FFPE to 2W TIL and REP TIL and confirmed that clonotypes with high frequencies in TILs have a high likelihood of maintaining their priority throughout culture process.

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Fig. 1: Clonal expansion and correlation of proportion in overlapped clones between FFPE and 2W TIL.
Fig. 2: Clonal expansion and correlation of proportion in overlapped clones between 2W TIL and REP TIL.
Fig. 3: Clonal expansion and correlation of proportion in overlapped clones between TCR clones in PBMC and other groups.
Fig. 4: Comparison between CD4+ and CD8+ T cells.
Fig. 5: Clonal fractions according to the in vitro reactivity.

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Data availability

Data are available on reasonable request.

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Funding

This study was supported by the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea (2018IL0169).

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Authors

Contributions

HJL and GG designed the study. BH, SYK, YAK, HJL, and JS developed the methodology. Experiments were performed by BH and YAK. Data were analyzed by BH, SYK, and JS. BH, SYK, YAK, HJL, and JS wrote the manuscript with input from all coauthors. DYH, TP, SC, SWJ, JHK, GP, and GG edited the manuscript.

Corresponding authors

Correspondence to Gyungyub Gong, Hee Jin Lee or Junyoung Shin.

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Competing interests

HJL is the CEO and owns stocks in NeogenTC Corp.

Ethics approval and consent to participate

This study was approved by the institutional review board of Asan Medical Center (approval no. 2016-0935), and written informed consent was obtained from the patients.

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Ham, B., Kim, S.Y., Kim, YA. et al. Persistence and enrichment of dominant T cell clonotypes in expanded tumor-infiltrating lymphocytes of breast cancer. Br J Cancer 131, 196–204 (2024). https://doi.org/10.1038/s41416-024-02707-6

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