Prospective identification of neoantigen-specific lymphocytes in the peripheral blood of melanoma patients

By A. Gros, M. Parkhurst, E. Tran, A. Pasetto, P. Robbins, Sadia Ilyas, Todd D Prickett, J. Gartner, J. Crystal, Ilana M. Roberts and 4 more. Nature Medicine, 2016

809 citations recorded by the source corpus.

Detection of lymphocytes that target tumor-specific mutant neoantigens—derived from products encoded by mutated genes in the tumor—is mostly limited to tumor-resident lymphocytes, but whether these lymphocytes often occur in the circulation is unclear. We recently reported that intratumoral expression of the programmed cell death 1 (PD-1) receptor can guide the identification of the patient-specific repertoire of tumor-reactive CD8+ lymphocytes that reside in the tumor. In view of these findings, we investigated whether PD-1 expression on peripheral blood lymphocytes could be used as a biomarker to detect T cells that target neoantigens. By using a high-throughput personalized screening approach, we identified neoantigen-specific lymphocytes in the peripheral blood of three of four melanoma patients. Despite their low frequency in the circulation, we found that CD8+PD-1+, but not CD8+PD-1−, cell populations had lymphocytes that targeted 3, 3 and 1 unique, patient-specific neoantigens, respectively. We show that neoantigen-specific T cells and gene-engineered lymphocytes expressing neoantigen-specific T cell receptors (TCRs) isolated from peripheral blood recognized autologous tumors. Notably, the tumor-antigen specificities and TCR repertoires of the circulating and tumor-infiltrating CD8+PD-1+ cells appeared similar, implying that the circulating CD8+PD-1+ lymphocytes could provide a window into the tumor-resident antitumor lymphocytes. Thus, expression of PD-1 identifies a diverse and patient-specific antitumor T cell response in peripheral blood, providing a novel noninvasive strategy to develop personalized therapies using neoantigen-reactive lymphocytes or TCRs to treat cancer.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/0b1fad17bc1aad583cefb60021d8e64dd9411d56

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Citations in the corpus

Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1–targeted therapy in lung cancer patients (2017, background): “Tumor-specific CD8 T cells are enriched among PD-1+ cells (20, 26), and have been identified among peripheral blood PD-1+ CD8 T cells in melanoma patients (27).”
Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids (2018, neutral): “, based on PD-1 expression by T cells (Gros et al., 2016).”
Neoantigens: promising targets for cancer therapy (2023, background): “Both circulating neoantigen-specific T cells and peripheral blood lymphocytes modified to express neoantigenspecific TCRs recognize and kill autologous malignancies.(467,496,497) There are several clinical trials utilizing neoantigen-reactive T cells generated from peripheral blood to treat patients”
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition (2021, positive): “Indeed, we obtained functional data from melanoma/gastric cancer patient tumor-infiltrating lymphocyte (TIL) samples, which were screened for reactivity against neoantigen peptides (Chudley et al., 2014; Gros et al., 2016; Tran et al., 2015), and found that T cell reactive epitopes had a significant”
T Cell Dysfunction in Cancer (2018, background): “This approach was successfully used to demonstrate the superior tumor recognition capacity of PD-1+ compared with PD-1 T cells in tumors and peripheral blood of melanoma patients (Gros et al., 2014, 2016).”
A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small cell lung cancer treated with PD-1 blockade (2018, neutral): “5 (2D1), -CD56 PE (CMSSB), - CD3 APC-eFluor780 (SK7), -Lag-3 FITC (3DS223H), -TIGIT PE (MBSA43), -2B4 FITC (eBioDM244), -CD137 FITC (4B4), -IL-2 PE (MQ1-17H12), -TNF-α APC (MAb11), - CD26 FITC (2A6), -CXCR5 Biotin (MU5UBEE), -ICOS FITC (ISA-3), -CD38 APC (HIT2), -Eomes eFluor660 (WD1928), -T-bet PE ”