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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]

Project description:TCR clonotypes in spleen and melanoma tumor from humanized mice.

2020-12-07 | GSE160885 | GEO

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.

| PRJNA677941 | ENA

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

Project description: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. [RNA-Seq]

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

| PRJNA677942 | ENA

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

Project description:Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.

| S-EPMC7804257 | biostudies-literature

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

Project description:Gene expression in 10 skin metastases from a patient with melanoma who had been treated with anti-PD-1 (Nivolumab) therapy was measured. Differences in gene expression between the lesions which responded to the treatment (n = 6) and the lesions which progressed (n = 4) were analyzed. Expression of certain genes associated with the extracellular matrix and with neutrophil function was found to be higher in the metastases which progressed. Insight into the biology governing response to immunotherapy may lead to improved rationally designed therapies, and to biomarkers for selecting patients who are more likely to benefit from these treatments.

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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

Project description:MAPK inhibitor (MAPKi) therapy in melanoma leads to accumulation of tumor-surface PD-L1/2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and down-regulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby modulating activation of co-cultured T cells. During MAPKi therapy in vivo, tumor cell-intrinsic ITCH knockdown in murine melanoma induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8+ T cells, and accelerated acquired resistance only in immune-proficient mice. Conversely, tumor cell-intrinsic ITCH over-expression reduced MAPKi-elicited PD-L1 accumulation, augmented cytolytic CD8+ T-cell infiltration, and suppressed acquired resistance in BrafMUT, NrasMUT, and Nf1MUT murine melanoma and KrasMUT pancreatic cancer models. CD8+ T-cell depletion and tumor cell-intrinsic PD-L1 over-expression nullified the ability of ITCH over-expression to suppress MAPKi-resistance, supporting in vivo the ITCH–PD-L1–T-cell regulatory axis demonstrated in human cancer cell lines. Moreover, we identified a small-molecular ITCH activator which suppressed acquired MAPKi-resistance in vivo. Thus, MAPKi-elicited tumor-surface PD-L1 accelerates acquired-resistance, and degrading PD-L1 by activating ITCH may be a combinatorial approach to promote antitumor T-cell immunity and durable responses.

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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