T Cells Expanded from PD-1+ Peripheral Blood Lymphocytes Share More Clones with Paired Tumor-Infiltrating Lymphocytes

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. Significance: 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

Tracking single cell evolution via clock-like chromatin accessibility

“…Particularly, we noticed that the tumor draining lymph node attraction markers CCR7 and SELL (CD62L) are expressed only in aged Tex, suggesting that they are recent migrate-in effector memory cells from draining lymph node (Figure 4e). Hence, in concordance with recent results with single cell TCR clonal tracing and clinical observations 48, 49 , our analysis suggest that peripheral influx of tumor-reactive T cells underly anti-PD1 response. Finally, we identified that cis-regulatory loci of a co-receptor and negative regulator of TGF-beta, CD109 (Figure 4f), and the nicotinic acetylcholine receptor CHRNA1 (Figure 4g), are specifically activated in response-associated Tex cells, suggesting novel targets for future research.…”

Clinical and immunological response to checkpoint therapy in renal cell carcinoma is associated with TCF1+ CD8 T-cells in the tumor

“…In comparison, patients who did not respond to treatment had a stable TCR repertoire where the most frequent clones before treatment maintained their dominance after therapy. Similarly, several studies have previously reported that response to checkpoint therapy is associated with new clones entering the total CD8 or the activated PD1+CD8 T-cell pool (22,41). Finally, we find that the T cell response in a patient's originally resected tumor (with surgery occurring months to years before receiving immunotherapy) predicts later response to checkpoint therapy, where patients with more CD8 T cells in their tumor exhibit improved responses to therapy.…”

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