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Cancer Neoepitopes for Immunotherapy: Discordance Between Tumor-Infiltrating T Cell Reactivity and Tumor MHC Peptidome Display
Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Karolinska Inst, Dept Pathol & Oncol, Stockholm, Sweden.
German Canc Res Ctr, Div Mol Oncol Gastrointestinal Tumors, Heidelberg, Germany.
Dana Farber Canc Inst, Lab Immunobiol, Boston, MA USA;Harvard Med Sch, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02115 USA;Harvard Med Sch, Dept Med, Boston, MA 02115 USA.
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2019 (English)In: Frontiers in Immunology, ISSN 1664-3224, E-ISSN 1664-3224, Vol. 10, article id 2766Article in journal (Refereed) Published
Abstract [en]

Tumor-infiltrating lymphocytes (TIL) are considered enriched for T cells recognizing shared tumor antigens or mutation-derived neoepitopes. We performed exome sequencing and HLA-A*02:01 epitope prediction from tumor cell lines from two HLA-A2-positive melanoma patients whose TIL displayed strong tumor reactivity. The potential neoepitopes were screened for recognition using autologous TIL by immunological assays and presentation on tumor major histocompatibility complex class I (MHC-I) molecules by Poisson detection mass spectrometry (MS). TIL from the patients recognized 5/181 and 3/49 of the predicted neoepitopes, respectively. MS screening detected 3/181 neoepitopes on tumor MHC-I from the first patient but only one was also among those recognized by TIL. Consequently, TIL enriched for neoepitope specificity failed to recognize tumor cells, despite being activated by peptides. For the second patient, only after IFN-gamma treatment of the tumor cells was one of 49 predicted neoepitopes detected by MS, and this coincided with recognition by TIL sorted for the same specificity. Importantly, specific T cells could be expanded from patient and donor peripheral blood mononuclear cells (PBMC) for all neoepitopes recognized by TIL and/or detected on tumor MHC-I. In summary, stimulating the appropriate inflammatory environment within tumors may promote neoepitope MHC presentation while expanding T cells in blood may circumvent lack of specific TIL. The discordance in detection between physical and functional methods revealed here can be rationalized and used to improve neoantigen-targeted T cell immunotherapy.

Place, publisher, year, edition, pages
2019. Vol. 10, article id 2766
Keywords [en]
TIL, tumor, Immune peptidome, neoepitopes, mass spectrometry, immunotherapy
National Category
Immunology in the medical area Immunology
Identifiers
URN: urn:nbn:se:uu:diva-402631DOI: 10.3389/fimmu.2019.02766ISI: 000505255100001PubMedID: 31921104OAI: oai:DiVA.org:uu-402631DiVA, id: diva2:1386421
Funder
Swedish Cancer Society, CAN2016/315Knut and Alice Wallenberg Foundation, KAW2015.0063Knut and Alice Wallenberg Foundation, 2013.0093Available from: 2020-01-17 Created: 2020-01-17 Last updated: 2020-01-17Bibliographically approved

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