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Pericancerous cross-presentation to cytotoxic T lymphocytes impairs immunotherapeutic efficacy in hepatocellular carcinoma
C Huang. et al.
Cancer Cell. 2024
This study investigated the phenotype, spatial distribution, and function of tumor-reactive cytotoxic T lymphocytes (CTLs) in hepatocellular carcinoma. Single-cell T cell sequencing, TCR sequencing, and spatial transcriptome analysis revealed that tumor-reactive CTLs predominantly exhibited a CD103+ tissue-resident phenotype, and their infiltration was surprisingly linked to tumor progression.
Further analysis indicated that the ratio of their distribution between the peritumoral and intratumoral regions effectively predicted patient response to immunotherapy. This suggests that the spatial distribution of CD103+ CTLs within the tumor microenvironment significantly influences their functional characteristics.
To explore the mechanism underlying CD103+ CTL retention in the peritumoral region, researchers found that their infiltration into tumor tissue primarily relied on the CXCR3 chemokine axis. Notably, peritumoral macrophages were the primary source of CXCR3 ligands in hepatocellular carcinoma. Cross-presentation by these macrophages activated CD103+ CTL proliferation and effector function, with IFN-γ secreted by CD103+ effector CTLs further enhancing macrophage activation and CXCR3 ligand expression. Conversely, tumor cells, due to high DNA methylation, exhibited significantly reduced expression of CXCR3 ligands, limiting their ability to recruit CD103+ CTLs. This combined effect resulted in the accumulation of CD103+ CTLs in the peritumoral region rather than their infiltration into the tumor.
Intriguingly, CD103+ CTLs activated by cross-presentation triggered the NLRP3 inflammasome in peritumoral macrophages through the perforin-calcium flux pathway. This led to IL-1β release, subsequent neutrophil recruitment, and angiogenesis, ultimately contributing to tumor progression and immunotherapy resistance.
Therefore, the retention of CD103+ CTLs in the peritumoral region, mediated by peritumoral macrophage cross-presentation, weakens intratumoral anti-tumor immunity and redirects the effector response of CD103+ CTLs toward a pathogenic inflammatory response. Based on these findings, the researchers proposed a combined therapeutic strategy targeting both the endogenous epigenetic silencing of tumor cells and the retention of CD103+ CTLs by peritumoral macrophages.
DOI: 10.1016/j.ccell.2024.10.012
02
C. E. Faliti. et al.
Immunity. 2024
The exact role of IL-2 in T cell help to B cells remains unclear despite the well-characterized functions of other Th cell-secreted cytokines like IL-21 and IL-4. B cells can differentiate into plasma cells (PCs) at extra-follicular (EF) sites or enter germinal centers (GCs) for affinity maturation. The work elucidated the role of IL-2 plays a crucial role in determining this fate by directly acting on B cells through the mTOR-AKT-Blimp-1 pathway.
Using a combination of in vivo mouse models, CRISPR-Cas9 gene editing, and in vitro culture systems, the study demonstrates that IL-2 signaling promotes EF PC differentiation while suppressing GC entry. IL-2 induces metabolic reprogramming in B cells, activating mTOR and upregulating key transcription factors like IRF4 and Blimp-1. This metabolic shift enhances early EF responses, leading to the generation of low-mutated plasma cells capable of robust antibody secretion.
Further experiments confirm that IL-2 acts intrinsically on CD25-expressing B cells to regulate their metabolic fitness and differentiation. The study also highlights the conservation of this IL-2-dependent mechanism in human B cells.
In conclusion, IL-2 serves as an early switch that guides B cell fate towards EF PC formation over GC-mediated affinity maturation. These findings have significant implications for understanding humoral immunity and designing immunotherapies targeting IL-2 signaling to enhance vaccine responses or regulate autoimmune conditions.
DOI: 10.1016/j.immuni.2024.11.006
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