Sagie and Babu et al. showed that antigen-specific killing of tumors by T cells expressing T104 – a novel, potent TCR specific for the HLA-A*03:01-restricted KRAS.G12V neoantigen – and by other neoantigen-specific T cells, TILs, and T cell-engager Abs, was boosted by lymphodepleting Cy-Flu chemotherapy-treated cultures at concentrations that minimized direct tumor cytotoxicity. Sublethal chemotherapy elevated immunoproteasome activity and HLA-I surface expression to increase the number, diversity, and hydrophobicity of therapeutically relevant neoantigen peptides for presentation in vitro and in tumors implanted s.c. into immunodeficient mice.
Contributed by Paula Hochman
ABSTRACT: Adoptive cell therapy (ACT) targeting tumor-specific antigens holds promise for solid tumors, but limited neoantigen presentation remains a key barrier to efficacy. Here, we identify and characterize a T cell receptor (TCR), T104, for the KRAS.G12V mutation, a prevalent neoantigen in colorectal, lung, and pancreatic cancers. TCR-T104 selectively recognizes and kills KRAS.G12V-expressing tumor cells. Combining T cell therapy with lymphodepleting chemotherapy significantly enhances tumor cell killing, particularly by TCR-T cells, tumor-infiltrating lymphocytes (TILs), and T cell engager antibodies across multiple cancer types and target antigens. Mechanistically, chemotherapy upregulates immunoproteasome activity and human leukocyte antigen (HLA)-I surface expression. HLA-immunopeptidome analyses reveal that chemotherapy remodels the antigenic landscape across tumor cell lines and in vivo models, increasing peptide abundance and hydrophobicity while altering proteasomal cleavage preferences. These findings establish a synergistic role for chemotherapy in enhancing neoantigen presentation and T cell-mediated tumor recognition and suggest that fine-tuning these regimens could improve ACT efficacy, particularly in tumors with low-abundance neoantigens.
Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel. (2) Departm
Author Info: (1) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel. (2) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (3) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (4) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (5) Rappaport Technion Cancer Research center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel; Institute of Pathology, Rambam Health Care Campus, Haifa 3109601, Israel. (6) Department of Statistics, University of Oxford, OX1 3LB Oxford, UK. (7) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (8) Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK. (9) Department of Statistics, University of Oxford, OX1 3LB Oxford, UK. (10) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (11) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (12) Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel. (13) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (14) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (15) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (16) Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK. (17) Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel. (18) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (19) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (20) Faculty of Medicine, Hadassah Hebrew-University Medical Center, Jerusalem 91120, Israel. (21) INCPM, Weizmann Institute of Science, Rehovot 7610001, Israel. (22) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (23) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (24) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (25) Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel. (26) Department of Systems Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. (27) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. (28) Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel; Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel. (29) Sharett Institute of Oncology, Hadassah Cancer Research Institute and The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. (30) Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK. (31) Department of Statistics, University of Oxford, OX1 3LB Oxford, UK. (32) Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: yardena.samuels@weizmann.ac.il.
