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.