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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE161353 | GEO | 2020/12/07

REPOSITORIES: GEO

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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. [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. [RNA-Seq]

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

2020-12-07 | GSE161351 | 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]

| PRJNA674781 | ENA

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

ZNF683 marks a CD8+ T cell population associated with anti-tumor immunity following anti-PD-1 therapy for Richter syndrome

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

2023-09-11 | GSE241091 | GEO

Tumor-associated macrophages-additional effectors at anti-PD-1/PD-L1 therapy?

Project description: Not available

| S-EPMC5720976 | biostudies-literature

PD-1<sup>+</sup> mast cell enhanced by PD-1 blocking therapy associated with resistance to immunotherapy.

Project description:BackgroundProgrammed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear.MethodsBioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo.ResultsBioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels.ConclusionPD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.

| S-EPMC9947072 | biostudies-literature

In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy.

Project description:Monoclonal antibodies (mAbs) targeting the immune checkpoint anti-programmed cell death protein 1 (aPD-1) have demonstrated impressive benefits for the treatment of some cancers; however, these drugs are not always effective, and we still have a limited understanding of the mechanisms that contribute to their efficacy or lack thereof. We used in vivo imaging to uncover the fate and activity of aPD-1 mAbs in real time and at subcellular resolution in mice. We show that aPD-1 mAbs effectively bind PD-1+ tumor-infiltrating CD8+ T cells at early time points after administration. However, this engagement is transient, and aPD-1 mAbs are captured within minutes from the T cell surface by PD-1- tumor-associated macrophages. We further show that macrophage accrual of aPD-1 mAbs depends both on the drug's Fc domain glycan and on Fc? receptors (Fc?Rs) expressed by host myeloid cells and extend these findings to the human setting. Finally, we demonstrate that in vivo blockade of Fc?Rs before aPD-1 mAb administration substantially prolongs aPD-1 mAb binding to tumor-infiltrating CD8+ T cells and enhances immunotherapy-induced tumor regression in mice. These investigations yield insight into aPD-1 target engagement in vivo and identify specific Fc/Fc?R interactions that can be modulated to improve checkpoint blockade therapy.

| S-EPMC5734617 | biostudies-literature

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