Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors
Philipp Beckhove, Markus Feuerer, Mathias Dolenc, Florian Schuetz, Carmen Choi, Nora Sommerfeldt, Jochen Schwendemann, Katrin Ehlert, Peter Altevogt, Gunther Bastert, Volker Schirrmacher, Viktor Umansky
Philipp Beckhove, Markus Feuerer, Mathias Dolenc, Florian Schuetz, Carmen Choi, Nora Sommerfeldt, Jochen Schwendemann, Katrin Ehlert, Peter Altevogt, Gunther Bastert, Volker Schirrmacher, Viktor Umansky
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Article Oncology

Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors

Abstract

Bone marrow of breast cancer patients was found to contain CD8+ T cells specific for peptides derived from breast cancer–associated proteins MUC1 and Her-2/neu. Most of these cells had a central or effector memory phenotype (CD45RA–CD62L+ or CD45RA–CD62L–, respectively). To test their in vivo function, we separated bone marrow–derived CD45RA+ naive or CD45RA–CD45RO+ memory T cells, stimulated them with autologous dendritic cells pulsed with tumor lysate, and transferred them into NOD/SCID mice bearing autologous breast tumors and normal skin transplants. CD45RA– memory but not CD45RA+ naive T cells infiltrated autologous tumor but not skin tissues after the transfer. These tumor-infiltrating cells had a central or effector memory phenotype and produced perforin. Many of them expressed the P-selectin glycoprotein ligand 1 and were found around P-selectin+ tumor endothelium. Tumor infiltration included cluster formation in tumor tissue by memory T cells with cotransferred dendritic cells. It was associated with the induction of tumor cell apoptosis and significant tumor reduction. We thus demonstrate selective homing of memory T cells to human tumors and suggest that tumor rejection is based on the recognition of tumor-associated antigens on tumor cells and dendritic cells by autologous specifically activated central and effector memory T cells.

Authors

Philipp Beckhove, Markus Feuerer, Mathias Dolenc, Florian Schuetz, Carmen Choi, Nora Sommerfeldt, Jochen Schwendemann, Katrin Ehlert, Peter Altevogt, Gunther Bastert, Volker Schirrmacher, Viktor Umansky

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TA specificity and function of BM memory T cells from breast cancer pati...
TA specificity and function of BM memory T cells from breast cancer patients. (A) T cells were stained with tetramers containing HLA-A2 and the MUC1 peptide LLLLTVLTV or the irrelevant HIV peptide SLYNTVATL. Representative data are shown. Blue, low density of cells; yellow, high density of cells. (B and C) Frequencies of MUC1- or Her-2/neu–specific CD8+ T cells from BM and PB of patients (P) and healthy donors (HD). Maximal levels of tetramer-binding CD8+ T cells from healthy donors are depicted by dotted lines. Frequencies of HIV-specific CD8+ T cells from BM and PB of nine breast cancer patients are shown. Maximum levels of nonspecific bindings are depicted by solid lines. (D) Accumulative data for MUC1- and Her-2/neu–binding CD8+ T cells expressing memory markers (seven and six patients, respectively). *P < 0.0001, memory versus naive cells; *P < 0.0001, EM versus CM cells. (E) Frequencies of Her-2/neu–specific BM T cells from patients or healthy donors, measured by IFN-γ ELISPOT after stimulation by DCs pulsed with the Her-2/neu peptide KIFGSLAFL. (F) MUC1-specific cytotoxicity of BM T cells. Patient (filled squares and filled triangles) or donor (open circles) cells were stimulated for 5 days with DCs pulsed with the MUC1 peptide LLLLTVLTV. HLA-A2+ T2 target cells were loaded with LLLLTVLTV (filled squares, open circles) or SLYNTVATL (filled triangles) peptides. X axis represents effector/target (E/T) ratios.