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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. [RNA-Seq]

ABSTRACT: Increased expression of mast cell related genes in melanoma tumors obtained from humanized mice after anti-PD-1 therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161351 | GEO | 2020/12/07

REPOSITORIES: GEO

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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. [TCR]

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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.

Project description:Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.

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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy. [TCR]

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Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy.

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-12-07 | GSE161353 | GEO

Transcriptional mechanisms of resistance to anti-PD-1 therapy

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Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance

Project description:Disrupting PD-1/PD-L1 interaction rejuvenates antitumor immunity. Clinical successes by blocking PD-1/PD-L1 binding have grown across wide-ranging cancer histologies, but innate therapy resistance is evident in the majority of treated patients1. Cancer cells can express robust surface levels of PD-L1 to tolerize tumor-specific T cells, but regulation of PD-L1 protein levels in the cancer cell is poorly understood. Quasi-mesenchymal tumor cells up-regulate PD-L1/L2 and induce an immune-suppressive microenvironment, including expansion of M2-like macrophages and regulatory T cells and exclusion of CD8+ T-cell infiltration2. Targeted therapy, including MAPK inhibitor therapy in melanoma, leads to quasi-mesenchymal transitions and resistance3, and both MAPK inhibitor treatment and mesenchymal signatures are associated with innate anti-PD-1 resistance4,5. Here we identify ITCH as an E3 ligase that downregulates tumor cell-surface PD-L1/L2 in PD-L1/L2-high cancer cells, including MAPK inhibitor-resistant melanoma, and suppresses acquired MAPK inhibitor resistance in and only in immune-competent mice. ITCH interacts with and poly-ubiquitinates PD-L1/L2, and ITCH deficiency increases cell-surface PD-L1/L2 expression and reduces T cell activation. Mouse melanoma tumors grow faster with Itch knockdown only in syngeneic hosts but not in immune-deficient mice. MAPK inhibitor therapy induces tumor cell-surface PD-L1 expression in murine melanoma, recapitulating the responses of clinical melanoma3, and this induction is more robust with Itch knockdown. Notably, suppression of ITCH expression first elicits a shift toward an immune-suppressive microenvironment and then accelerates resistance development. These findings collectively identify ITCH as a critical negative regulator of PD-L1 tumor cell-surface expression and provide insights into previously unexplained role of PD-L1 in adaptive resistance to therapy.

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Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresses Acquired Resistance

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2022-05-31 | GSE199733 | GEO

Role of B cells in generating anti-melanoma immunity in response to anti-PD-L1 antibody therapy

Project description:B cells potentially play a role in the immune response to melanoma, including during treatment with immune modulators. We profiled (transcriptome analysis) effects of anti-PD-L1 antibody therapy on gene expression in B16 melanoma tumors of B cells depleted and WT syngeneic mice. After 7 days of B16 tumors implantation, mice were treated or untreated with anti-PD-L1 antibody (every three days).

2022-05-15 | GSE202879 | GEO

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