Spatial Profile of Tumor Microenvironment in PD-L1-Negative and PD-L1-Positive Triple-Negative Breast Cancer

Abstract

The problem of finding more precise stratification criteria for identifying the cohort of patients who would obtain the maximum benefit from immunotherapy is acute in modern times. In our study were enrolled 18 triple-negative breast cancer patients. The Ventana SP142 test was used for PD-L1 detection. Spatial transcriptomic analysis by 10x Genomics was used to compare PD-L1-positive and PD-L1-negative tumors. The seven-color multiplex immunofluorescence (by Akoya) was used for the detection of the type of cells that carried the PD1 receptor and the PD-L1 ligand. Using pathway analysis, we showed that PD-L1-positive tumors demonstrate signatures of a cell response to cytokines, among others, and PD-L1-negative tumors demonstrate signatures of antigen presentation. PD-L1-positive and PD-L1-negative tumors have different tumor microenvironment (TME) compositions according to CIBERSORT analysis. Multiplex immunohistochemistry (IHC) confirmed the prevalence of PD1-negative M2 macrophages and PD1-negative T lymphocytes in PD-L1-positive tumors. PD-L1-positive tumors are not characterized by direct contact between cells carrying the PD1 receptor and the PD-L1 ligand. So, the absence of specific immune reactions against the tumor, predominance of pro-tumor microenvironment, and rare contact between PDL1 and PD1-positive cells may be the potential reasons for the lack of an immune checkpoint inhibitor (ICI) effect in triple-negative breast cancer patients.

Macrophage diversity in human cancers: New insight provided by single-cell resolution and spatial context

“…Spatial transcriptomics analysis using 10x Genomics Visium was applied to study PD-L1-positive and PD-L1-negative tumors from patients with TNBC [ 127 ]. The profile of PD-L1-negative tumors that had higher infiltration of M0 macrophages was characterized by the expression of CD163 , HLA-A , and STAB1 .…”

“…The profile of PD-L1-negative tumors that had higher infiltration of M0 macrophages was characterized by the expression of CD163 , HLA-A , and STAB1 . In contrast, PD-L1-positive tumors had an elevated level of M2 macrophages, and the following marker genes: IL1R2 , CHI3L2 , and CHI3L1 [ 127 ].…”

Advances in spatial transcriptomics and its applications in cancer research

“…These findings open new avenues for improving TNBC treatment strategies and personalizing therapy. In addition, Tashireva et al investigated differences in the spatial distribution of the TME in PD-L1-negative and PD-L1-positive TNBC, highlighting the prevalence of PD1-negative M2 macrophages and PD1-negative T lymphocytes in PD-L1-positive tumors [120]. This may be the underlying reason why patients with TNBC do not benefit from ICI.…”

Deciphering the tumour immune microenvironment cell by cell

“…Importantly, PD-1-positive cells did not interact with PD-L1-expressing cells, consistent with the poor efficacy of ICIs in this cancer. 29 …”