What question did this study set out to answer?

This research aims to determine if the spatial proximity between PD-L1(+) TAMs and CD8(+) T cells impacts response to Atezo+Bev in hepatocellular carcinoma.

May 4, 2026Open Access

Spatial Proximity Between PD-L1(+) Tumor-Associated Macrophages and CD8(+) T Cells Influences Response to Atezolizumab Plus Bevacizumab in Hepatocellular Carcinoma

Key Points

This research aims to determine if the spatial proximity between PD-L1(+) TAMs and CD8(+) T cells impacts response to Atezo+Bev in hepatocellular carcinoma.
Conducted multiplex immunohistochemistry on biopsies from 23 patients treated with Atezo+Bev and 20 with lenvatinib.
Defined an interaction variable through nearest-neighbor analysis to assess proximity of CD8(+) T cells to PD-L1(+) TAMs.
Performed transcriptomic profiling on resected HCC samples using next-generation sequencing.
Closer proximity of PD-L1(+) TAMs to CD8(+) T cells correlated with tumor shrinkage and prolonged progression-free survival (PFS) in the Atezo+Bev group.
High-interaction tumors exhibited increased GZMB(+) and TIM3(+) CD8(+) T cells.
Transcriptomic analysis indicated upregulation of key immune-related genes and enriched signaling pathways.

Abstract

Background: Responses to atezolizumab plus bevacizumab (Atezo+Bev) in hepatocellular carcinoma (HCC) are heterogeneous, and response determinants remain unclear. We investigated whether spatial proximity between PD-L1(+) tumor-associated macrophages (TAMs) and CD8(+) T cells represents an immune niche associated with Atezo+Bev responsiveness. Methods: Multiplex immunohistochemistry was performed on biopsies from patients treated with Atezo+Bev (n = 23) or lenvatinib (n = 20). An interaction variable was defined via nearest-neighbor analysis as CD8(+) T cells within 25 µm of PD-L1(+) TAMs, normalized to cell counts. Associations with tumor shrinkage and progression-free survival (PFS) were examined. CD8(+) T cell phenotypes were evaluated via GZMB and TIM3. Transcriptomic profiling of resected HCCs (n = 8) was conducted using next-generation sequencing and gene set enrichment analysis (GSEA). Results: In a patient with responsive and non-responsive lesions, the responsive lesion showed closer PD-L1(+) TAM-CD8(+) T cell proximity. In cohort analyses, the interaction variable was associated with tumor shrinkage and prolonged PFS in the Atezo+Bev group, whereas PD-L1(+) TAM or CD8(+) T cell density alone was not predictive. This association was absent in the lenvatinib cohort. High-interaction tumors showed increased GZMB(+) and TIM3(+) CD8(+) T cells. Transcriptomic analysis revealed the upregulation of inflammatory, cytotoxic, chemotactic, and immunoregulatory genes, with enrichment of the chemokine, IFN-gamma, and IL-10 signaling pathways. Conclusions: Spatial proximity between PD-L1(+) TAMs and CD8(+) T cells defines an immune niche characterized by coexisting immune activation and regulatory programs and is strongly associated with Atezo+Bev responsiveness in HCC. Quantification of this spatial interaction may serve as a biopsy-based biomarker for immunotherapy stratification.

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