Characterising the preferential suppression of potent anti-tumour CTL responses by regulatory T cells

The ability to generate potent anti-tumour CTL responses is fundamental to the rejection of many tumours. However many potent anti-tumour responses are suppressed by regulatory T cells. The removal of this Treg suppression in the CT26 tumour model uncovers potent cryptic anti-GSW11 CTL, which become immunodominant. I characterise the GSW11-specific response and compare these with responses against the anti-tumour AH1-specific T cells, a representative of the global T cell population in both Treg depleted and replete tumour challenged mice. I show that the majority of CD8+ T cells recruited to the tumour site in Treg replete mice are GSW11-specific. Interestingly, the vast majority of these GSW11-specific T cells are in a PD1+ clonally exhausted state and thus unable to clear the tumour. I also show that the percentage of clonally exhausted cells, and the levels of PD1 on GSW11-specific T cells are much greater compared to AH1-specific T cells, thus indicating preferential suppression among CTL populations. Furthermore, my data revealed this phenomenon was also present in the draining lymph node during T cell priming following CT26 tumour challenge. Investigation of differences in TCR Vß usage revealed expansion of particular Vß families over others in the absence of Treg. This work highlights the complex interplay between peripheral tolerance mechanisms and CTL, which selectively hinders protective anti-tumour immunity.