Abstract
Background
The clinical significance of adoptive tumor-infiltrating lymphocyte (TIL) therapy has been demonstrated in many clinical trials. We analyzed the in vitro reactivity of cultured TILs against autologous breast cancer cells.
Methods
TILs and cancer cells were cultured from 31 breast tumor tissues. Reactivity of TILs against cancer cells was determined by measuring secreted interferon-gamma. Expression levels of epithelial markers, major histocompatibility complex molecules, and programmed death-ligand 1 (PD-L1) in cancer cells, and T cell markers (memory, T cell activation and exhaustion, and regulatory T cell markers) in expanded TILs were analyzed and compared between the reactive and non-reactive groups.
Results
In seven cases, TILs showed reactivity to autologous cancer cells. Six of these cases were associated with triple-negative breast cancer (TNBC). All reactive TNBCs were derived from surgical specimens after neoadjuvant chemotherapy (NAC). Higher expression of Ki67 in tumor tissues and lower expression of PD-L1 in cultured cancer cells were associated with reactivity. Proliferation of reactive TILs was high. High proportions of T cells and PD-1+CD4+ and PD1+CD8+ T cells were associated with reactivity in TNBC cases, while other activation or exhaustion markers were not.
Conclusion
TILs from approximately half the TNBC cases with NAC showed reactivity against autologous cancer cells. The proportion of PD-1+ T cells was higher in the reactive group. Adoptive TIL therapy combined with PD-1 inhibitors might be promising for TNBC patients with residual tumors after NAC.
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Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- ACT:
-
Adoptive cell transfer
- CK:
-
Cytokeratin
- EpCAM:
-
Epithelial cell adhesion molecule
- ER:
-
Estrogen receptor
- HER2+ :
-
Human epidermal growth factor receptor 2-positive
- HR:
-
Hormone receptor
- IFN-γ:
-
Interferon-gamma
- MDSCs:
-
Myeloid-derived suppressor cells
- MHC:
-
Major histocompatibility complex
- NAC:
-
Neoadjuvant chemotherapy
- NK:
-
Natural killer
- NKT:
-
Natural killer T
- PBMC:
-
Peripheral blood mononuclear cell
- PDX:
-
Patient-derived xenograft
- PR:
-
Progesterone receptor
- REP:
-
Rapid expansion
- TCR:
-
T cell receptor
- TIL:
-
Tumor-infiltrating lymphocyte
- TLS:
-
Tertiary lymphoid structure
- TNBC:
-
Triple-negative breast cancer
- Treg:
-
Regulatory T cell
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Funding
This study was supported by the Korean Health Technology R&D Project, Ministry of Health & Welfare (HI15C0708 and HI17C0337) and the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea (2018IL0169, 2019IL0169, and 2019IL0839).
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HjL interpreted the data associated with tumor-infiltrating lymphocyte reactivity in breast cancer and was a major contributor in writing the manuscript. YAK and HSP participated in sample preparation and analysis. YK and JHS analyzed the TCR repertoire of the TILs. HL, GG, and HJL contributed as pathologists and revised the manuscript. All authors read and approved the final manuscript.
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Tumor tissues were obtained from patients along with their consent to the use of the specimen for research purposes. This study was approved by the Institutional Review Board of Asan Medical Center (IRB#2015-0438).
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Lee, H., Kim, YA., Kim, Y. et al. Clinicopathological factors associated with tumor-infiltrating lymphocyte reactivity in breast cancer. Cancer Immunol Immunother 69, 2381–2391 (2020). https://doi.org/10.1007/s00262-020-02633-5
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DOI: https://doi.org/10.1007/s00262-020-02633-5