Chun and Park et al. looked at the effects of in situ FLTL3 expression and PD-1 inhibition on cDC1s and CD8+ T cells in the tumor microenvironment. Asialo-ganglio-N-tetraosylceramide (asGM1) expression was found to differentiate Tpex CD8+ T cells (asGM1neg) and Tex CD8+ T cells (asGM1pos). Both therapies selectively expanded intratumoral CD8+ T cells, increased expression of Tpex and Teffector-like genes, and promoted the selective expansion and differentiation of asGM1neg into asGM1pos CD8+ T cells via cDC1-derived IL-12. However, only FLT3L enhanced clonal diversification and broadened the T cell repertoire.
Contributed by Katherine Turner
ABSTRACT: PD-1 blockade enhances anti-tumoral CD8(+) T cell responses via type 1 conventional dendritic cells (cDC1s), but how cDC1s change the properties of intratumoral CD8(+) T cells remains to be determined. Here, we identified two populations of intratumoral CD8(+) T cells distinguished by their expression of asialo-ganglio-N-tetraosylceramide (asGM1). asGM1(neg) and asGM1(pos)CD8(+) T cells show enriched expression of genes characteristic for precursor exhausted T (Tpex) cells and terminally exhausted T (Tex) cells, respectively. The in situ expression of Flt3L or inhibition of PD-1 each promote the differentiation of asGM1(neg)CD8(+) T cells into asGM1(pos)CD8(+) T cells via interleukin-12 (IL-12) while also increasing the expression of Tpex and effector-like T cell-associated genes and their effector functions. Both interventions selectively expand CD8(+) T cells, but only Flt3L expression broadens their T cell receptor (TCR) repertoire. These data indicate the distinct role of Flt3L in diversifying the TCR repertoire, offering potential solutions for immune checkpoint blockade-resistant cancers.
