Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion
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PROVIDER: PRJNA1036166 | ENA |
REPOSITORIES: ENA
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Project description:Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc]
| PRJNA1036175 | ENA
Project description:Temporal genomic analysis of melanoma rejection identifies regulators of tumor immune evasion [scc35]
| PRJNA1036174 | ENA
Project description:Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogenous tumors may display variability in their aggressiveness, and how immunologic-factors impinge on their aggressiveness remains understudied. Here we studied the mechanisms responsible for the immune-escape of murine tumors with low ITH. We compared the temporal growth of homogeneous, genetically-similar single-cell clones that are rejected vs. those that are not-rejected after transplantation in-vivo using single-cell RNA sequencing and immunophenotyping. Non-rejected clones showed high infiltration of tumor-associated-macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate mediators, identified Mif (macrophage migration inhibitory factor) as a regulator of immune rejection. Mif knockout led to smaller tumors and reversed non-rejection-associated immune composition, particularly, leading to the reduction of immunosuppressive macrophage infiltration. Finally, we validated these results in melanoma patient data.
| S-EPMC10705560 | biostudies-literature
Project description:Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, the mechanism underlying this association remains inconclusive since additional factors dictate tumor aggressiveness. Here, we study the mechanisms responsible for the immune escape of tumors bearing low ITH. We compare homogeneous, genetically similar single-cell clones that are rejected vs. non-rejected after transplantation. We followed the growth of these clone-derived tumors over time using single-cell RNA sequencing and immunophenotyping. Non-rejected clones show high infiltration of tumor-associated macrophages (TAM), increased Mif expression, lower T-cell infiltration, and increased T-cell exhaustion. Mif KO led to smaller tumors and reversed these immune phenotypes, validating its role in the growth of low ITH tumors. Mif secretion by these tumor cells causes TAM infiltration, thus contributing to an immunosuppressive environment that supports aggressive growth. We validated this result in melanoma patient data, confirming that high levels of MIF distinguish aggressive from non-aggressive ITHs.
2023-12-12 | GSE247058 | GEO
Project description:Decreased intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, the mechanism underlying this association remains inconclusive since additional factors dictate tumor aggressiveness. Here, we study the mechanisms responsible for the immune escape of tumors bearing low ITH. We compare homogeneous, genetically similar single-cell clones that are rejected vs. non-rejected after transplantation. We followed the growth of these clone-derived tumors over time using single-cell RNA sequencing and immunophenotyping. Non-rejected clones show high infiltration of tumor-associated macrophages (TAM), increased Mif expression, lower T-cell infiltration, and increased T-cell exhaustion. Mif KO led to smaller tumors and reversed these immune phenotypes, validating its role in the growth of low ITH tumors. Mif secretion by these tumor cells causes TAM infiltration, thus contributing to an immunosuppressive environment that supports aggressive growth. We validated this result in melanoma patient data, confirming that high levels of MIF distinguish aggressive from non-aggressive ITHs.
2023-12-12 | GSE247057 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-12-12 | GSE247059 | GEO
Project description:The ubiquitin-proteasome system maintains protein homeostasis, underpins the cell cycle and is dysregulated in cancer. However, the role of individual E3 ubiquitin ligases, which mediate the final step in ubiquitin-mediated proteolysis, remains incompletely understood. Identified through screening for cancer-specific endogenous retroviral transcripts, we show that the little studied E3 ubiquitin ligase HECTD2 exerts dominant control of tumour progression in melanoma. HECTD2 cell-autonomously drives the proliferation of human and murine melanoma cells by accelerating the cell cycle. HECTD2 additionally regulates cancer cell production of immune mediators, initiating multiple immune suppressive pathways, which include the cyclooxygenase 2 (COX2) pathway. Accordingly, higher HECTD2 expression is associated with weaker anti-tumour immunity and unfavourable outcome of PD-1 blockade in human melanoma, and counteracts immunity against a model tumour antigen in murine melanoma. This central, multifaceted role of HECTD2 in cancer cell-autonomous proliferation and in immune evasion may provide a single target for a multipronged therapy of melanoma.
2021-07-23 | PXD025237 | Pride
Project description:Although genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent immune signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. Loss of SMARCAL1 enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a valuable target for cancer immunotherapy.
2024-01-24 | PXD046384 | Pride
Project description:Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation
| PRJNA1076516 | ENA
Project description:Genomic instability can trigger cancer-intrinsic innate immune responses that promote tumor rejection. However, cancer cells often evade these responses by overexpressing immune checkpoint regulators, such as PD-L1. Here, we identify the SNF2-family DNA translocase SMARCAL1 as a factor that favors tumor immune evasion by a dual mechanism involving both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. Mechanistically, SMARCAL1 relieves endogenous DNA damage and suppresses cGAS-STING-dependent signaling during cancer cell growth. Simultaneously, it cooperates with the AP-1 family member JUN to maintain chromatin accessibility at a transcriptional regulatory element in the PD-L1 gene, thereby promoting PD-L1 expression in cancer cells. SMARCAL1 loss hinders the ability of tumor cells to induce PD-L1 in response to genomic instability, enhances anti-tumor immune responses and sensitizes tumors to immune checkpoint blockade in a mouse melanoma model. Collectively, these studies uncover SMARCAL1 as a promising target for cancer immunotherapy.
2024-01-22 | GSE245449 | GEO