scholarly journals Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Dennis Doleschel ◽  
Sabine Hoff ◽  
Susanne Koletnik ◽  
Anne Rix ◽  
Dieter Zopf ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Treg Cells ◽  
Drug Synergism ◽  
Drug Discontinuation ◽  
Multikinase Inhibitor ◽  
Colon Cancers ◽  
Sustained Effects ◽  
Tumor Regrowth

Abstract Background Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism. Methods Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses. Results In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression. Conclusions This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors.

When Neighbors Talk: Colon Cancer Cell Invasion and Tumor Microenvironment Myofibroblasts

2017 ◽  
Vol 18 (8) ◽  
pp. 964-982 ◽  
Author(s):  
Jolien Bridelance ◽  
Zuzanna Drebert ◽  
Olivier De Wever ◽  
Marc Bracke ◽  
Ilse M. Beck
Keyword(s):  
Colon Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Colon Cancer Cell ◽  
Cancer Cell Invasion

scholarly journals Activation of the GPR35 pathway drives angiogenesis in the tumour microenvironment

Gut ◽  
2021 ◽  
pp. gutjnl-2020-323363
Author(s):  
Ester Pagano ◽  
Joshua E Elias ◽  
Georg Schneditz ◽  
Svetlana Saveljeva ◽  
Lorraine M Holland ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumour Growth ◽  
Tumour Microenvironment ◽  
Tube Formation ◽  
Tissue Remodelling ◽  
Colon Cancers ◽  
Inflammatory Bowel ◽  
Ion Pumping ◽  
G Protein Coupled

ObjectivePrimary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers.DesignMice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays.ResultsHere, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors.ConclusionsActivation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.

scholarly journals FOXP3 expression accurately defines the population of intratumoral regulatory T cells that selectively accumulate in metastatic melanoma lesions

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4953-4960 ◽  
Author(s):  
Mojgan Ahmadzadeh ◽  
Aloisio Felipe-Silva ◽  
Bianca Heemskerk ◽  
Daniel J. Powell ◽  
John R. Wunderlich ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Metastatic Melanoma ◽  
Treg Cell ◽  
Peripheral Blood ◽  
Ex Vivo ◽  
Production Capacity ◽  
Biological Marker ◽  
Foxp3 Expression ◽  
Treg Cells

Abstract Regulatory T (Treg) cells are often found in human tumors; however, their functional characteristics have been difficult to evaluate due to low cell numbers and the inability to adequately distinguish between activated and Treg cell populations. Using a novel approach, we examined the intracellular cytokine production capacity of tumor-infiltrating T cells in the single-cell suspensions of enzymatically digested tumors to differentiate Treg cells from effector T cells. Similar to Treg cells in the peripheral blood of healthy individuals, tumor-infiltrating FOXP3+CD4 T cells, unlike FOXP3− T cells, were unable to produce IL-2 and IFN-γ upon ex vivo stimulation, indicating that FOXP3 expression is a valid biological marker for human Treg cells even in the tumor microenvironment. Accordingly, we enumerated FOXP3+CD4 Treg cells in intratumoral and peritumoral sections of metastatic melanoma tumors and found a significant increase in proportion of FOXP3+CD4 Treg cells in the intratumoral compared with peritumoral areas. Moreover, their frequencies were 3- to 5-fold higher in tumors than in peripheral blood from the same patients or healthy donors, respectively. These findings demonstrate that the tumor-infiltrating CD4 Treg cell population is accurately depicted by FOXP3 expression, they selectively accumulate in tumors, and their frequency in peripheral blood does not properly reflect tumor microenvironment.

517 Regulatory T cell functional identity is sustained by a glucose:lactate axis that is exploited in the tumor microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
McLane Watson ◽  
Paolo Vignali ◽  
Steven Mullet ◽  
Abigail Overacre-Delgoffe ◽  
Ronal Peralta ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Treg Cell ◽  
High Glucose ◽  
Cell Function ◽  
Treg Cells ◽  
Effector T Cells ◽  
Flux Analysis ◽  
Major Barrier ◽  
Suppressive Function

BackgroundRegulatory T (Treg) cells are vital for preventing autoimmunity but are a major barrier to robust cancer immunity as the tumor microenvironment (TME) recruits and promotes their function. The deregulated cellular metabolism of tumor cells leads to a metabolite-depleted, hypoxic, and acidic TME. While the TME impairs the effector function of highly glycolytic tumor infiltrating CD8 T cells, Treg cell suppressive function is maintained. Further, studies of in vitro induced and ex vivo Treg cells reveal a distinct metabolic profile compared to effector T cells. Thus, it may be that the altered metabolic landscape of the TME and the increased activity of intratumoral Treg cells are linked.MethodsFlow cytometry, isotopic flux analysis, Foxp3 driven Cre-lox, glucose tracers, Seahorse extracellular flux analysis, RNA sequencing.ResultsHere we show Treg cells display heterogeneity in terms of their glucose metabolism and can engage an alternative metabolic pathway to maintain their high suppressive function and proliferation within the TME and other tissues. Tissue derived Treg cells (both at the steady state and under inflammatory conditions) show broad heterogeneity in their ability to take up glucose. However, glucose uptake correlates with poorer suppressive function and long-term functional stability, and culture of Treg cells in high glucose conditions decreased suppressive function. Treg cells under low glucose conditions upregulate genes associated with the uptake and metabolism of the glycolytic end-product lactic acid. Treg cells withstand high lactate conditions, and lactate treatment prevents the destabilizing effects of high glucose culture. Treg cells utilize lactate within the TCA cycle and generate phosphoenolpyruvate (PEP), a critical intermediate that can fuel intratumoral Treg cell proliferation in vivo. Using mice with a Treg cell-restricted deletion of lactate transporter Slc16a1 (MCT1) we show MCT1 is dispensable for peripheral Treg cell function but required intratumorally, resulting in slowed tumor growth and prolonged survival.ConclusionsThese data support a model in which Treg cells are metabolically flexible such that they can utilize ‘alternative’ metabolites present in the TME to maintain their suppressive identity. Further, our studies support the notion that tumors avoid immune destruction not only by depriving effector T cells of essential nutrients, but also by metabolically supporting regulatory T cells.

scholarly journals Age-related inequalities in colon cancer treatment persist over time: a population-based analysis

2018 ◽  
Vol 73 (1) ◽  
pp. 34-41 ◽  
Author(s):  
Louise Hayes ◽  
Lynne Forrest ◽  
Jean Adams ◽  
Mira Hidajat ◽  
Yoav Ben-Shlomo ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Treatment ◽  
Treatment Decision ◽  
Population Based ◽  
Surgical Patients ◽  
Area Deprivation ◽  
Treatment Decision Making ◽  
Colon Cancers ◽  
Age Related ◽  
Over Time

BackgroundOlder people experience poorer outcomes from colon cancer. We examined if treatment for colon cancer was related to age and if inequalities changed over time.MethodsData from the UK population-based Northern and Yorkshire Cancer Registry on 31 910 incident colon cancers (ICD10 C18) diagnosed between 1999–2010 were obtained. Likelihood of receipt of: (1) cancer-directed surgery, (2) chemotherapy in surgical patients, (3) chemotherapy in non-surgical patients by age, adjusting for sex, area deprivation, cancer stage, comorbidity and period of diagnosis, was examined.ResultsAge-related inequalities in treatment exist after adjustment for confounding factors. Patients aged 60– 69, 70–79 and 80+ years were significantly less likely to receive surgery than those aged <60 years (multivariable ORs (95% CI) 0.84(0.74 to 0.95), 0.54(0.48 to 0.61) and 0.19(0.17 to 0.21), respectively). Age-related differences in receipt of surgery and adjuvant chemotherapy (but not chemotherapy in non-surgical patients) narrowed over time for the ’younger old’ (aged <80 years) but did not diminish for the oldest patients.ConclusionsAge inequality in treatment of colon cancer remains after adjustment for confounders, suggesting age remains a major factor in treatment decisions. Research is needed to better understand the cancer treatment decision-making process, and how to influence this, for older patients.

scholarly journals Ibrutinib-Induced Vasculitis in a Patient with Metastatic Colon Cancer Treated in Combination with Cetuximab

2020 ◽  
Vol 2020 ◽  
pp. 1-4 ◽  
Author(s):  
Jeffrey Chi ◽  
Jennifer Park ◽  
Muhammad Wasif Saif
Keyword(s):  
Colon Cancer ◽  
Growth Factor ◽  
Combination Therapy ◽  
Growth Factor Receptor ◽  
Hematologic Malignancies ◽  
Hair Follicles ◽  
Metastatic Colon Cancer ◽  
Egfr Inhibitor ◽  
Gastrointestinal Malignancies ◽  
Btk Inhibitor

Combination therapy with ibrutinib and cetuximab is being studied in a phase 1b/2 trial in patients with advanced gastrointestinal and genitourinary malignancies. Rash is a common cutaneous adverse effect for both medications. Ibrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor approved for the treatment of several hematologic malignancies. The rash can be asymptomatic, nonpalpable, mild skin eruption, or palpable purpuric rash. A rarer panniculitis form has also been reported. Cetuximab, an epidermal growth factor (EGFR) inhibitor, approved for treatment in head and neck and advanced gastrointestinal malignancies is also known to cause acneiform rash in majority of patients. The rash is due to inhibition of EGFR in the basal keratinocytes and hair follicles. In the case of ibrutinib, the off-target effects on EGFR, c-kit, and platelet-derived growth factor receptor (PDGFR) are thought to be responsible for the cutaneous eruption of various forms of rash. The combination therapy with the BTK inhibitor and a direct EGFR inhibitor may potentiate the rash inducing effects of the drugs. Here, we describe a case of vasculitis in a patient with metastatic colon cancer who received both ibrutinib and cetuximab on a phase Ib/II clinical trial.

B234 Dasatinib and Dexamethasone Combination Therapy Targets Myeloma and the Tumor Microenvironment

2009 ◽  
Vol 9 ◽  
pp. S116-S117
Author(s):  
KA Ramasamy ◽  
L Macpherson ◽  
G Mufti ◽  
S Schey ◽  
Y Calle
Keyword(s):  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Therapy Targets

scholarly journals Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma

2017 ◽  
Vol 6 (10) ◽  
pp. 2308-2320 ◽  
Author(s):  
Hiroyuki Kitano ◽  
Yasuhiko Kitadai ◽  
Jun Teishima ◽  
Ryo Yuge ◽  
Shunsuke Shinmei ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Targeted Drugs

scholarly journals Alteration in the immune microenvironment based on APC status in MSS/pMMR colon cancer data retrieved from TCGA

2020 ◽  
Author(s):  
Haishan Lin ◽  
Hongchao Zhen ◽  
Kun Shan ◽  
Xiaoting Ma ◽  
Bangwei Cao
Keyword(s):  
Colon Cancer ◽  
Cancer Patients ◽  
Enrichment Analysis ◽  
Tumor Immunotherapy ◽  
Immune Checkpoints ◽  
Immune Microenvironment ◽  
Cancer Data ◽  
T Cell Infiltration ◽  
Colon Cancers ◽  
Tumor Immune Microenvironment

Abstract Immunotherapy is currently the most advanced anti-tumor treatment approach. The efficacy of anti-tumor immunotherapy is closely related to the tumor immune microenvironment, including immune cells, infiltration of immune factors, and expression of immune checkpoints. At present, the biomarkers for predicting the efficacy of colon cancer immunotherapy do not cover all colon cancer patients suitable for immunotherapy. In this study, TCGA database was used to identify tumor genotypes suitable for anti-tumor immunotherapy. We found that some of the MSS/pMMR populations, that were initially considered unsuitable for immunotherapy, might actually be suitable. In APC-wt/MSS colon cancer, the expression of PD-1, PD-L1, CTLA4 and CYT（GZMA and PRF1）were increased. Based on calculations done by ESTIMATE and CIBERSORT algorithms, the ImmunoScore and the proportion of CT8+ T cell infiltration is increased in these patients. Enrichment analysis was done to screen signaling pathways involved in immune response, extracellular matrix, and cell adhesion. Tumors from 42 colon cancer patients, including 22 APC-mt/MSS and 20 APC-wt/MSS, were immunohistochemically evaluated for expression of CD8 and PD-L1. And APC-wt/MSS tumors showed significantly higher expression of CD8 and PD-L1 than APC-mt/MSS tumor. Based on the results, we found that some colon cancers of APC-wt/MSS are classified by Tumor Immune Microenvironment types (TIMTs) TMIT I. So that we speculate that APC-wt/MSS colon cancer patients could benefit from anti-tumor immunotherapy.

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