title: Loss of CTL function among high-avidity tumor-specific CD8+ T cells following tumor infiltration.
abstract: A major problem in generating effective antitumor CTL responses is that most tumors express self-antigens to which the immune system is rendered unresponsive due to mechanisms of self-tolerance induction. CTL precursors (CTLp) expressing high-affinity T-cell receptors (TCR) are often functionally deleted from the repertoire, leaving a residual repertoire of CTLp having only low-affinity TCR. Furthermore, even when unique antigens are expressed, their presentation by dendritic cells (DC) may predispose to peripheral tolerance induction rather than the establishment of CTL responses that kill tumor cells. In this study, we examined both high-avidity (CL4) and low-avidity (CL1) CD8(+) T-cell responses to a murine renal carcinoma expressing, as a neoantigen, high and low levels of the hemagglutinin (HA) protein from influenza virus A/PR/8 H1N1 (PR8; RencaHA(high) and RencaHA(low)). Our data show that, following encounter with K(d)HA epitopes cross-presented by bone marrow-derived DC, low-avidity CL1 cells become tolerized within tumor-draining lymph nodes (TDLN), and in mice bearing either RencaHA(high) or RencaHA(low) tumors, very few form tumor-infiltrating lymphocytes (TIL). In marked contrast, high-avidity CL4 cells differentiate into effector CTL within the TDLN of mice bearing either RencaHA(high) or RencaHA(low) tumors, and although they form TIL in both tumors, they lose CTL effector function. Critically, these results show that anticancer therapies involving either adoptive transfer of high-avidity tumor-specific CTL populations or targeting of preexisting tumor antigen-specific memory CD8(+) T cells could fail due to the fact that CTL effector function is lost following tumor infiltration.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences, Bristol, United Kingdom.
authors.forename: Claire N
authors.initials: CN
authors.lastname: Janicki
authors.forename: S Rhiannon
authors.initials: SR
authors.lastname: Jenkinson
authors.forename: Neil A
authors.initials: NA
authors.lastname: Williams
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgan
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000032:analysis; D007680:Kidney Neoplasms / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D018183:Transplantation Chimera
chemical_list: D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma