TdLN-resident HHEX+ progenitor CD8+ T cells reinforce checkpoint response and CAR-T durability in solid tumors [CUT&Tag, ATAC-seq]

ABSTRACT: Tumor‑specific stem‑like CD8+ TPEX cells initially differentiate in tumor-draining lymph nodes (TdLNs) and display heterogeneous stemness, yet intrinsic CD8+ T‑cell regulators governing their specification from TdLNs to tumors remain unclear. Integrating human NSCLC scRNA‑seq and mouse lineage tracing, we identify HHEX+ antigen-experienced CD8+ T progenitors in TdLNs. These cells possess prominent memory‑like features and efficiently replenish intratumoral cytotoxic TPEX upon tumor re‑challenge, and respond favorably to PD‑1/PD‑L1 blockade. In humanized NCG mice bearing with solid tumors, CD8+ CAR T cells infusion with overexpression of human HHEX almost completely controlled tumor growth, and protected the humanized mice against tumors recurrence. Human HHEX overexpression dramatically increased the proportion of memory-like CD62L+ CD8+ CAR T cells in tumors. Mechanistically, HHEX+ progenitors in TdLNs exhibited a higher proportion of HHEX+ TCF1+ double positive cells relative to tumors, HHEX interacts with TCF1 to maintain memory-like gene program with increasing chromatin accessibility. Loss of Hhex leads to an increased proportion of terminally exhausted CD8+ T cells, memory-like associated genes were markedly down-regulated in tumors, including CD62L. Collectively, our findings underscore the pivotal role of Hhex in the development of memory-like CD8+ T cells, thereby ensuring sustained anti-tumor immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE354174 | GEO | 2026/11/11

REPOSITORIES: GEO