Roles of tumour localization, second signals and cross priming in cytotoxic T-cell induction

The vertebrate immune system has evolved to protect against infections that threaten survival before reproduction. Clinically manifest tumours mostly arise after the reproductive years and somatic mutations allow even otherwi se antigenic tumours to evade the attention of the immune system(1-3). More over, the lack of immunological co-stimulatory molecules on solid tumours c ould result in T-cell tolerance(4-8); that is, the failure of T cells to re spond. However, this may not generally apply(9,10). Here we report several important findings regarding the immune response to tumours, on the basis o f studies of several tumour types. First, tumour-specific induction of prot ective cytotoxic T cells (CTLs) depends on sufficient tumour cells reaching secondary lymphatic organs early and for a long enough duration. Second, d iffusely invading systemic tumours delete CTLs. Third, tumours that stay st rictly outside secondary lymphatic organs, or that are within these organs but separated from T cells by barriers, are ignored by T cells but do not d elete them. Fourth, co-stimulatory molecules on tumour cells do not influen ce CTL priming but enhance primed CTL responses in peripheral solid tumours . Last, cross priming of CTLs by tumour antigens, mediated by major histoco mpatibility complex (MHC) class I molecules of antigen-presenting host cell s, is inefficient and not protective. These rules of T-cell induction and m aintenance not only change previous views but also rationales for anti-tumo ur immunotherapy(1,2).