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Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s

ABSTRACT: T-cell exclusion from the tumor microenvironment (TME) is a significant obstacle in cancer immunotherapy. Evidence indicates crucial roles of Batf3-dependent dendritic cells for inducing antitumor T-cell immunity. However, strategies to maximize the engagement of Batf3-dependent dendritic cells into such ‘cold tumors’ remain elusive. Using multiple syngeneic orthotopic mouse models of non-T cell-inflamed tumors, we hypothesized that in situ induction and activation of tumor-residing Batf3-dependent dendritic cells overcomes poor T-cell infiltration. In situ immunomodulation with Flt3L, radiotherapy, and TLR3/CD40 stimulation induces an influx of stem-like Tcf1+Slamf6+CD8+ T cells, triggers robust regression not only of primary, but also untreated distant tumors, and renders non-T cell-inflamed tumors responsive to anti-PD-L1 therapy. Furthermore, serial ISIM reshapes repertoires of intratumoral T cells, overcomes acquired resistance to anti-PD-L1 therapy, resulting in eradication of tumors, and establishes tumor-specific immunological memory. These findings provide new insights into Batf3-dependent dendritic cells biology as a critical determinant to the formation of a T cell-inflamed TME.

ORGANISM(S): Mus musculus

PROVIDER: GSE154879 | GEO | 2020/09/24

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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Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing cDC1s

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