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Background: CD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T‐cell‐mediated immunity. However, the role of CD70 in B‐cell malignancies remains controversial. Methods: We investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B‐cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD‐L1 inhibitor in a murine lymphoma model. Results: We showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over‐expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high‐expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD‐L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells. Conclusions: Our findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno‐therapeutic strategies. [ABSTRACT FROM AUTHOR]

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8+ T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis. [Display omitted] • Multi-regional and multi-omic profiles of paired primary and metastatic HCC tumors • Polyclonal, early dissemination and APM defects result in high ITH in metastases • Wnt-wt subclones show stronger selection for metastasis than Wnt-mut counterparts • Focal and arm-level SCNA deletion events are genomic drivers of HCC metastasis Sun et al. characterize multi-regional and multi-omics (genomics, transcriptomics, scRNA-seq, spatial transcriptomics, and IHC) profiles for paired primary and metastatic hepatocellular carcinoma from 182 patients. They reveal high intratumor heterogeneity in metastatic HCCs, complex evolutionary trajectories, subclonal selection, and crucial roles of tumor microenvironment (cancer-associated fibroblast and B cells) during metastasis. [ABSTRACT FROM AUTHOR]