Box plot shows the percentage of CD45RA-CD62L+, CD45RA- CD62L-, CD45RA+ CD62L+, and CD45RA+ CD62L- T cells in the subset of CD4+ (A and E, PD-1-T cells; B and F, PD-1+T cells )and CD8+ (C and G, PD-1-T cells; D and H, PD-1+T cells ) T cells before (Upper panel, n=4) and after (Lower panel, n=8) expansion with the protocol established in this study.
Funding
National Natural Science Foundation of China
Henan Medical Science and Technique Foundation
Henan Provincial Scientific and Technological Project
History
ARTICLE ABSTRACT
Both tumor-infiltrating lymphocytes (TIL) and PD-1+ peripheral blood lymphocytes (PBL) are enriched for tumor-reactive clones recognizing known and unknown tumor antigens. However, the relationship between the T-cell receptor-β (TCRβ) repertoires of the TILs and T cells expanded from paired PD-1+ PBLs, and whether T cells expanded from PD-1+ PBLs can be used to treat patients with cancer as TIL substitutes remain unclear. Here, we established a highly efficient protocol to prepare polyclonal T cells from PD-1+ PBLs. A functional T-cell assay and tetramer staining revealed that cells from PD-1+ PBLs were relatively enriched for tumor-reactive T cells. Furthermore, deep TCRβ sequencing data revealed that an average of 11.29% (1.32%–29.06%; P = 0.015; n = 8) tumor-resident clonotypes were found in T cells expanded from paired PD-1+ PBLs, and the mean accumulated frequency of TIL clones found in T cells expanded from PD-1+ PBLs was 35.11% (7.23%–78.02%; P = 0.017; n = 8). Moreover, treatment of four patients, who failed multiline therapy and developed acquired resistance to anti-PD-1, with autologous T cells expanded from PD-1+ PBLs combined with anti-PD-1 antibody elicited objective responses from three of them. These results indicate that T cells expanded from PD-1+ PBLs share more clones with paired TILs and could be used to treat patients with cancer as TIL substitutes.
This study harnesses the tumor reactivity of PD-1+ PBLs, developing a method to expand T cells from these clones as a potential therapeutic strategy and TIL substitute in patients with cancer.See related commentary by Ladle, p. 1940