Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA710489 | ENA |
REPOSITORIES: ENA
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Project description:Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors leading to reduced immune surveillance in NSCLC is critical in improving patient outcomes. Here, we show that human NSCLC harbors large amounts of fibrosis that correlates with reduced T cell infiltration. In murine NSCLC models, the induction of fibrosis led to increased lung cancer progression, impaired T cell immune surveillance, and failure of immune checkpoint blockade efficacy. Associated with these changes, we observed that fibrosis leads to numerically and functionally impaired dendritic cells and altered macrophage phenotypes that likely contribute to immunosuppression. Within cancer-associated fibroblasts, distinct changes within the Col13a1-expressing population suggest that these cells produce chemokines to recruit macrophages and regulatory T cells while limiting recruitment of dendritic cells and T cells. Targeting fibrosis through transforming growth factor-β receptor signaling overcame the effects of fibrosis to enhance T cell responses and improved the efficacy of immune checkpoint blockade but only in the context of chemotherapy. Together, these data suggest that fibrosis in NSCLC leads to reduced immune surveillance and poor responsiveness to checkpoint blockade and highlight antifibrotic therapies as a candidate strategy to overcome immunotherapeutic resistance.
2023-06-29 | GSE227534 | GEO
Project description:Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here we show in a metastatic CRC multi-tumor preclinical model that orthotopically-implanted primary colon tumors can spontaneously exert a colon-specific and immune-dependent antimetastatic effect on distant hepatic lesions. An immune signature, integrating antitumor CD8 T cells, dendritic cells and protumor macrophages, that we called MicroEnvironment (ME)-score, was predictive of the antimetastatic effect. ScRNA-Seq and phenotypic analyses revealed that enterotropic α4β7 integrin expressing tumor neoantigen-specific CD8 T cells were key components of the systemic immune response responsible for the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved the efficacy of proof-of-concept ICB on liver lesions and generated a protective memory immune response whereas antibody-mediated partial depletion of α4β7+ cells abrogated the control of metastatic disease by the primary tumor. Finally, in a metastatic CRC patients’ cohort, we show increased expression of genes encoding the α4β7 integrin and of the ME-score in ICB responsive metastases concomitant with increased proportions of circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut primed tumor-specific α4β7+ CD8 T cells.
2023-11-01 | GSE219087 | GEO
Project description:Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here we show in a metastatic CRC multi-tumor preclinical model that orthotopically-implanted primary colon tumors can spontaneously exert a colon-specific and immune-dependent antimetastatic effect on distant hepatic lesions. An immune signature, integrating antitumor CD8 T cells, dendritic cells and protumor macrophages, that we called MicroEnvironment (ME)-score, was predictive of the antimetastatic effect. ScRNA-Seq and phenotypic analyses revealed that enterotropic α4β7 integrin expressing tumor neoantigen-specific CD8 T cells were key components of the systemic immune response responsible for the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved the efficacy of proof-of-concept ICB on liver lesions and generated a protective memory immune response whereas antibody-mediated partial depletion of α4β7+ cells abrogated the control of metastatic disease by the primary tumor. Finally, in a metastatic CRC patients’ cohort, we show increased expression of genes encoding the α4β7 integrin and of the ME-score in ICB responsive metastases concomitant with increased proportions of circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut primed tumor-specific α4β7+ CD8 T cells.
2023-11-01 | GSE193593 | GEO
Project description:Despite the high prognostic value of immune infiltrates in colorectal cancer (CRC), metastatic disease remains resistant to immunotherapy by immune checkpoint blockade (ICB). Here we show in a metastatic CRC multi-tumor preclinical model that orthotopically-implanted primary colon tumors can spontaneously exert a colon-specific and immune-dependent antimetastatic effect on distant hepatic lesions. An immune signature, integrating antitumor CD8 T cells, dendritic cells and protumor macrophages, that we called MicroEnvironment (ME)-score, was predictive of the antimetastatic effect. ScRNA-Seq and phenotypic analyses revealed that enterotropic α4β7 integrin expressing tumor neoantigen-specific CD8 T cells were key components of the systemic immune response responsible for the antimetastatic effect. Accordingly, the presence of concomitant colon tumors improved the efficacy of proof-of-concept ICB on liver lesions and generated a protective memory immune response whereas antibody-mediated partial depletion of α4β7+ cells abrogated the control of metastatic disease by the primary tumor. Finally, in a metastatic CRC patients’ cohort, we show increased expression of genes encoding the α4β7 integrin and of the ME-score in ICB responsive metastases concomitant with increased proportions of circulating α4β7+ CD8 T cells. Our findings identify a systemic cancer immunosurveillance role for gut primed tumor-specific α4β7+ CD8 T cells.
2023-11-01 | GSE193534 | GEO
Project description:We examined how the immune microenvironment molds tumor evolution in a longitudinal dataset of colorectal cancer liver metastases. Through multiplexed analyses, the immune microenvironment exerts a strong selection pressure during treatment of CLM tumor. Increasing infiltration of T cell were associated with favorable outcomes and sensitive response to chemotherapy ± Bevacizumab. Activation of fatty acid metabolism, xenobiotic metabolism, insulin receptor signaling pathway and neutrophils infiltration were observed in progressive tumors. TCR diversity in response metastatic regions was significantly increased compared with non-responder. Bevacizumab containing regimen facilitated T cell infiltrating to the tumor microenvironment which might consequently benefit from checkpoint immunotherapy. In responding patients, mutation load from plasma were reduced from baseline, but changed slightly in tumor tissues. This integrative and comparative omics analysis provides a new paradigm for understanding the evolution and treatment resistance of colorectal cancer liver metastases, with implications for identifying ways to advance treatment regimen and monitoring treatment response of colorectal cancer liver metastases.
2020-03-08 | GSE136114 | GEO
Project description:Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need.
2023-09-27 | GSE221359 | GEO
Project description:Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need.
2023-10-17 | GSE245453 | GEO
Project description:Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need.
2023-09-27 | GSE221357 | GEO
Project description:Immune checkpoint blockade has limited efficacy in microsatellite stable (MSS) colorectal (CRC) and pancreatic (PDAC) cancer. Preclinical models have demonstrated the use of radiation to activate the innate immune response and stimulate responsiveness to immune checkpoint blockade. Here, we describe a Phase 2 trial of radiation therapy combined with combined anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) antibodies in MSS CRC and PDAC. In the per protocol analysis disease control rate was 37% (10/27) in CRC and 29% (5/17) in PDAC with an overall response rate of 15% (4/27) and 18% (3/17), respectively. Whole exome and RNA sequencing of biopsies from 17 patients revealed low tumor mutational burden in all tumors, but a notable upregulation of interferon stimulated genes with concordant high expression of multiple repeat RNA transcripts in responders. Altogether, this study provides foundational human proof of concept of radiation with combination immune checkpoint blockade therapy in otherwise immunotherapy resistant cancers.
2021-07-06 | GSE179351 | GEO
Project description:Comparison of genomic alterations of primary colorectal cancers with liver metastases of the same patient Keywords: array CGH, colorectal cancer, colon cancer, liver metastasis 21 primary colorectal cancers and 21 matched liver metastases hybridized against sex-matched control pools
2010-07-07 | E-GEOD-10179 | biostudies-arrayexpress