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

Abstract

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 otherwise antigenic tumours to evade the attention of the immune system. Moreover, the lack of immunological co-stimulatory molecules on solid tumours could result in T-cell tolerance; that is, the failure of T cells to respond. However, this may not generally apply. Here we report several important findings regarding the immune response to tumours, on the basis of studies of several tumour types. First, tumour-specific induction of protective cytotoxic T cells (CTLs) depends on sufficient tumour cells reaching secondary lymphatic organs early and for a long enough duration. Second, diffusely invading systemic tumours delete CTLs. Third, tumours that stay strictly 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 delete them. Fourth, co-stimulatory molecules on tumour cells do not influence CTL priming but enhance primed CTL responses in peripheral solid tumours. Last, cross priming of CTLs by tumour antigens, mediated by major histocompatibility complex (MHC) class I molecules of antigen-presenting host cells, is inefficient and not protective. These rules of T-cell induction and maintenance not only change previous views but also rationales for anti-tumour immunotherapy.

Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes

“…Six weeks later, we confirmed that CXCR3 protein continued to be expressed in the transplanted cells by immunohistochemistry (Figure 4a), and examined macroscopically metastatic foci of the para-aortic LNs using GFP fluorescence. Interestingly, the mice inoculated not only with DLD-1-CXCR3 cells, but also with DLD-1-EV cells showed macroscopic enlargement of the para-aortic LNs, which reflects that sensitized immune cells can reach LNs and cause proliferative reactions (Ochsenbein et al, 2001). However, under a fluorescence dissection microscope, we found that DLD-1-CXCR3 cells metastasized to LNs with a significantly higher frequency than DLD-1-EV (Figure 4b).…”

Targeting tumors with LIGHT to generate metastasis-clearing immunity

“…However, tumor stroma may hinder T cell priming by sequestering antigenic tumor cells, thus preventing them from reaching the DLN to directly prime a T cell response [17]. In such an event, cross-presentation by professional APCs, often DCs, from the tumor tissues becomes a major pathway for naïve T cells to be primed tumor antigens.…”

Suppression of murine tumour growth through CD8+ cytotoxic T lymphocytes via activated DEC‐205+ dendritic cells by sequential administration of α‐galactosylceramide in vivo

“…Moreover, the priming and activation of antigen‐specific CD8 + CTLs required co‐stimulatory signalling via CD80 and CD86 10. Hence, CD8 + CTLs, which are tumour‐specific, can be primed and activated by tumour‐antigen‐loaded activated DEC‐205 + DCs expressing co‐stimulatory molecules 11, 12…”