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Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T-cell evasion in triple negative breast cancer

ABSTRACT: Only a subgroup of triple-negative breast cancer (TNBC) responds to immune checkpoint inhibitors (ICI). To better understand lack of response to ICI, we analyzed 681 TNBCs for spatial immune cell contextures in relation to clinical outcomes as well as pathways of T-cell evasion. Excluded, ignored and inflamed phenotypes were captured by a gene classifier that predicts prognosis of various cancers as well as anti-PD1 response of metastatic TNBC patients in a phase II trial. The excluded phenotype, which was associated with resistance to anti-PD1, demonstrated deposits of collagen-10, enhanced glycolysis, and activation of TGFb/VEGF pathways; the ignored phenotype, also associated with resistance to anti-PD1, showed either high density of CD163+ myeloid cells or activation of WNT/PPARg pathways; whereas the inflamed phenotype, which was associated with response to anti-PD1, revealed necrosis, high density of CLEC9A+ dendritic cells, high TCR clonality independent of neo-antigens, and enhanced expression of T-cell co-inhibitory receptors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE177043 | GEO | 2021/06/12

REPOSITORIES: GEO

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Project description:Background:Acral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. Methods: We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. Results: 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3 + CD8 + PD1 + intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low vs high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared to responders across cancers, including acral melanoma, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. Conclusions: A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

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Spatial immunophenotypes predict response to anti-PD1 treatment and capture distinct paths of T-cell evasion in triple negative breast cancer

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