Magen and Hamon et al. analyzed surgically resected tumor lesions and matched, non-involved adjacent liver tissues from HCC patients with T cell-rich tumors to identify molecular correlates of response to neoadjuvant ICB therapy. PD-1hi effector CD8+ T cells and CXCL13+ TH cells were preferentially clonally expanded in tumors of responders, whereas a subset of T cell-rich tumors that failed to respond to anti-PD-1 showed increases in PD-1hi terminal CD8+ T cells and Tregs. T cell clones that expanded upon PD-1 blockade were present in tumor lesions before treatment, and PD-1hi progenitor CD8+ T cells were enriched in close proximity to mregDC/CXCL13+ TH niches in responders.
Contributed by Shishir Pant
ABSTRACT: Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13(+)CH25H(+)IL-21(+)PD-1(+)CD4(+) T helper cells ("CXCL13(+) T(H)") and Granzyme K(+) PD-1(+) effector-like CD8(+) T cells, whereas terminally exhausted CD39(hi)TOX(hi)PD-1(hi)CD8(+) T cells dominated in nonresponders. CD4(+) and CD8(+) T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1(+)TCF-1(+) (Progenitor-exhausted) CD8(+) T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8(+) T cell differentiation occurs upon ICB. We found that these Progenitor CD8(+) T cells interact with CXCL13(+) T(H) within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13(+) T(H) control the differentiation of tumor-specific Progenitor exhasuted CD8(+) T cells following ICB.