Targeting Focal Adhesion Kinase Renders Pancreatic Cancers Responsive to Checkpoint Immunotherapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE75233 | GEO | 2015/11/21
SECONDARY ACCESSION(S): PRJNA302854
REPOSITORIES: GEO
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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
2015-11-21 | E-GEOD-75233 | biostudies-arrayexpress
Project description:Pancreatic ductal adenocarcinoma(PDAC) is a highly lethal malignancy with poor response rate to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have been implicated as drivers of resistance to both conventional and immune therapies. As such, targeting RAS/MAPK signaling is an attractive strategy. However, in practice, MAPK inhibition has not yet shown clinical efficacy, likely due to rapid acquisition resistance in PDAC cells. Tumor intrinsic mechanisms of resistance to RAS/MAPK have been studied, however, the unique PDAC TME may also be a key driver in resistance. Previous studies have shown that FAK inhibition can reprogram the PDAC TME and delay PDAC progression in animal models. Herein, we found that long-term FAK inhibitor treatment leads to hyperactivation of the MAPK pathway in both genetically engineered mouse models and in post-treatment PDAC tissues from FAK inhibitor clinical trials. Concomitant inhibition of both FAK (VS4718) and RAF/MEK (V6766) signaling dramatically suppressed tumor cell growth, leading to increased survival across multiple PDAC mouse models. The mechanisms of synergy include both changes in tumor-intrinsic signaling and modulation of tumor/stroma interactions that drive MEK resistance. In the TME, we found that cancer associated fibroblasts (CAFs) can impair the downregulation of cMyc by MEK inhibition in PDAC cells. This results in de-novo resistance to MEK inhibition in fibrotic conditions. By contrast, FAK inhibitors reprogram CAFs to suppress the production of key growth factors, including FGF1, that drives resistance to RAF/MEK inhibition. While combined FAK and RAF/MEK inhibition only leads to disease stasis, the addition of chemotherapy to the combination led to tumor regression and improved long-term survival in PDAC mouse models. Analysis of tumor immunity showed that the combination of FAK and MEK inhibition improved anti-tumor immunity and improved priming of T cell responses, which was further improved with the addition of chemotherapy. These findings led to testing of FAK (Defactinib) plus RAF/MEK (Avutometinib) inhibition in combination with gemcitabine and nab-paclitaxel in advanced pancreatic cancer patients (NCT05669482). Finally, we tested if the addition of immunotherapy could enhance the efficacy of the FAKi/MEKi/chemotherapy and found adding in either PD1 or CTLA4/PD1 blockade led to long term disease control in PDAC animal models. Together, these studies identified novel FAK inhibition as a route to overcome both tumor intrinsic and stromal-derived resistance to MAPK inhibition and showed that this combination can be exploited to increase the efficacy of cytotoxic and immunotherapy approaches.
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Project description:Pancreatic ductal adenocarcinoma(PDAC) is a highly lethal malignancy with poor response rate to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have been implicated as drivers of resistance to both conventional and immune therapies. As such, targeting RAS/MAPK signaling is an attractive strategy. However, in practice, MAPK inhibition has not yet shown clinical efficacy, likely due to rapid acquisition resistance in PDAC cells. Tumor intrinsic mechanisms of resistance to RAS/MAPK have been studied, however, the unique PDAC TME may also be a key driver in resistance. Previous studies have shown that FAK inhibition can reprogram the PDAC TME and delay PDAC progression in animal models. Herein, we found that long-term FAK inhibitor treatment leads to hyperactivation of the MAPK pathway in both genetically engineered mouse models and in post-treatment PDAC tissues from FAK inhibitor clinical trials. Concomitant inhibition of both FAK (VS4718) and RAF/MEK (V6766) signaling dramatically suppressed tumor cell growth, leading to increased survival across multiple PDAC mouse models. The mechanisms of synergy include both changes in tumor-intrinsic signaling and modulation of tumor/stroma interactions that drive MEK resistance. In the TME, we found that cancer associated fibroblasts (CAFs) can impair the downregulation of cMyc by MEK inhibition in PDAC cells. This results in de-novo resistance to MEK inhibition in fibrotic conditions. By contrast, FAK inhibitors reprogram CAFs to suppress the production of key growth factors, including FGF1, that drives resistance to RAF/MEK inhibition. While combined FAK and RAF/MEK inhibition only leads to disease stasis, the addition of chemotherapy to the combination led to tumor regression and improved long-term survival in PDAC mouse models. Analysis of tumor immunity showed that the combination of FAK and MEK inhibition improved anti-tumor immunity and improved priming of T cell responses, which was further improved with the addition of chemotherapy. These findings led to testing of FAK (Defactinib) plus RAF/MEK (Avutometinib) inhibition in combination with gemcitabine and nab-paclitaxel in advanced pancreatic cancer patients (NCT05669482). Finally, we tested if the addition of immunotherapy could enhance the efficacy of the FAKi/MEKi/chemotherapy and found adding in either PD1 or CTLA4/PD1 blockade led to long term disease control in PDAC animal models. Together, these studies identified novel FAK inhibition as a route to overcome both tumor intrinsic and stromal-derived resistance to MAPK inhibition and showed that this combination can be exploited to increase the efficacy of cytotoxic and immunotherapy approaches.
2024-09-04 | GSE247547 | GEO
Project description:Autotaxin (ATX), encoded by ENPP2, catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME). ATX is a clinical target in pancreatic ductal adenocarcinoma (PDAC), yet the pro-tumorigenic action of the ATX/LPA axis in PDAC remains unclear. PDAC is characterized by a highly fibrotic tumor microenvironment (TME) due to an abundance of cancer associated fibroblasts (CAFs), acting as a barrier to therapy and contributing to the poor survival of PDAC patients. The mechanism by which ATX inhibition influences CAFs and their secretome is still not fully characterized. To identified potential downstream mediators of ATX signaling, we performed RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors, IOA-289 and PF-8380. PF-8380 treatment resulted in a higher number of differentially expressed genes compared to IOA-289 treatment. IOA-289 treatment resulted in only four significantly differentially expressed genes (CTGF, PLIN2, HHIP, and AHNAK). However, only PLIN2, which was upregulated and CTGF, which was downregulated, overlapped between the two ATX inhibitors. As CTGF (connective tissue growth factor) is a pro-fibrotic and pro-tumorigenic factor, it suggests a key role for CAF-derived ATX in promoting autocrine and paracrine pro-tumorigenic signaling in PDAC.
2024-10-06 | E-MTAB-14494 | biostudies-arrayexpress
Project description:Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant immunosuppressive and fibrotic tumor microenvironment (TME). Future therapeutic attempts therefore demand targeting of both compartments in order to be effective. We show here that Dual Specificity and Tyrosine Phosphorylation-regulated Kinase 1B (DYRK1B) represents a compartment-agnostic anti-cancer target in PDAC. DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as affecting the tumor secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and in addition downregulates the phagocytosis checkpoint and "don't eat me"-signal CD24 on cancer cells, resulting in enhanced tumor cell phagocytosis. Consequently, tumor cells lacking DYRK1B hardly expand in transplantation experiments despite doing so rapidly in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mTOR inhibition and conventional chemotherapy stalls the growth of established tumors and results in significant extension of life span in a highly aggressive autochthonous model of PDAC. In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting the cancer cell compartment and its microenvironment, both.
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2020-04-01 | GSE144507 | GEO
Project description:Cancer-associated fibroblasts (CAFs), although considered as the most abundant pancreatic ductal adenocarcinoma (PDAC) stromal cells playing a critical role in tumor progression and chemoresistance, are not yet directly druggable. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK-kinase-dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumor and dramatically decreases tumor spread. Mechanistically, pharmacologic and genetic fibroblastic FAK inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumor cell invasion.
2020-08-19 | PXD018899 | Pride
Project description:With the advent of cancer immunotherapy, intense investigation has been focused on tumor-infiltrating immune cells. With only a fraction of patients responding to these new therapies, a better understanding of all elements of the tumor microenvironment (TME) that may influence therapeutic outcome is needed. Stromal elements of the TME, chiefly fibroblasts, have emerged as potential contributors to tumor progression and most recently resistance to immunotherapy, but their precise composition and clinical relevance remain incompletely understood. Here we use single-cell transcriptomics to chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models, identifying two healthy tissue fibroblast subsets that co-evolve along individual trajectories into four subsets of carcinoma-associated fibroblasts (CAFs).
2019-10-31 | E-MTAB-8483 | biostudies-arrayexpress
Project description:Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in mouse monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
2020-05-01 | GSE144609 | GEO
Project description:Retinoic acid signaling regulates monocyte differentiation into dendritic cells or macrophages. We used microarrays to uncover gene expression changes associated with retinoic acid exposure in human monocytes. The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor associated macrophages (TAMs) but not immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we found that the TME induced retinoic acid (RA) production by tumor cells, which polarized intratumoral monocyte differentiation towards TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production by tumor cells or pharmacologic inhibition of RA signaling within TME increased stimulatory monocyte-derived cells, enhanced T cell-dependent anti-tumor immunity and demonstrated striking synergy with immune checkpoint blockade. Further, RA responsive gene signature in human monocytes correlated with an immunosuppressive TME in multiple human tumors. RA has been long considered as an anti-cancer agent, but our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.
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