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.
Author Info: (1) Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (2) Department of Biological Sciences, Korea Advanced I
Author Info: (1) Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (2) Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (3) Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (4) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (5) Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. (6) Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. Electronic address: suk-jo.kang@kaist.ac.kr.
