Imprinting of Lymphocytes with Melanoma Antigens Acquired by Trogocytosis Facilitates Identification of Tumor-Reactive T Cells

Abstract

Trogocytosis is a contact-dependent inter-cellular transfer of membrane fragments and associated molecules from antigen presenting cells to effector lymphocytes. We previously demonstrated that trogocytosis also occurs between tumor target and cognate melanoma antigen-specific cytotoxic T cells (CTL). Here we show that, following trogocytosis, immune effector cells acquire molecular components of the tumor, including surface antigens, which are detectable by specific monoclonal antibodies. We demonstrate that CD8+ and CD4+ T cells from melanoma patients’ PBMC and tumor infiltrating lymphocytes (TIL) capture melanoma antigens, enabling identification of trogocytosing lymphocytes by staining with antigen-specific antibodies. This finding circumvents the necessity of tumor pre-labeling, which in the past was mandatory to detect membrane-capturing T cells. Through the detection of melanoma antigens on TIL, we sorted trogocytosing T cells and verified their preferential reactivity and cytotoxicity. Furthermore, tumor-antigen imprinted T cells were detected at low frequency in fresh TIL cultures shortly after extraction from the tumor. Thus, T cell imprinting by tumor antigens may allow the enrichment of melanoma antigen-specific T cells for research and potentially even for the adoptive immunotherapy of patients with cancer.

Antigen-Specific Inhibition of High-Avidity T Cell Target Lysis by Low-Avidity T Cells via Trogocytosis

“…The Jacobson and Lotem groups demonstrated that trogocytosis could be used to detect and isolate antigen-specific CTLs via either transfer of pMHC complexes (Tomaru et al, 2003), membrane (Machlenkin et al, 2008), or surface antigens (Eisenberg et al, 2013). Using trogocytosis and signaling analysis, the Lotem group also demonstrated that a peptide-specific (MART26-35) TIL response consisted of individual T cells with different functional responses (Uzana et al, 2012), consistent with our previous findings that only high avidity TAA-specific T cells could kill tumor cells (Stuge et al, 2004).…”

Trogocytosis-Mediated Intracellular Signaling in CD4+ T Cells Drives TH2-Associated Effector Cytokine Production and Differentiation

“…This phenomenon is not exclusive to T cells, as B cells (16,17), NK cells (18)(19)(20), basophils (21), macrophages (22,23), neutrophils (24)(25)(26), and dendritic cells (27,28) have all been reported to perform trogocytosis. With elevated levels of trogocytosis documented in sites of autoimmune inflammation (29), viral and parasitic infections (30)(31)(32), rheumatoid arthritis (33), and tumor environments (34,35), this widely observed event has been proposed to play a role in the modulation of immune responses (27,(36)(37)(38)(39)(40)(41).…”

Autologous Tumor Vaccine Modified with Recombinant New Castle Disease Virus Expressing IL-7 Promotes Antitumor Immune Response

“…Cytotoxic CD8 + T cells are considered to be the major player in cancer immunotherapy. The increased proportion of tumor-infiltrating T lymphocytes has been found to correlate with improved clinical outcome in several human cancers, such as ovarian cancer, melanoma, and prostate cancer (48)(49)(50). We further demonstrated that the antitumor immunity conferred by the tumor cells modified with LX/(IL-7) was associated with the enhancement of CD8 + T cell functions.…”