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The molecular mechanisms regulating CD8+ cytotoxic T lymphocytes (CTL) are not fully understood. Here, we show that the peroxisome proliferator-activated receptor δ (PPARδ) suppresses CTL cytotoxicity by inhibiting RelA DNA binding. Treatment of ApcMin/+ mice with the PPARδ agonist GW501516 reduced the activation of normal and tumor-associated intestinal CD8+ T cells and increased intestinal adenoma burden. PPARδ knockout or knockdown in CTLs increased their cytotoxicity against colorectal cancer cells, whereas overexpression of PPARδ or agonist treatment decreased it. Correspondingly, perforin, granzyme B, and IFNγ protein and mRNA levels were higher in PPARδ knockout or knockdown CTLs and lower in PPARδ overexpressing or agonist-treated CTLs. Mechanistically, we found that PPARδ binds to RelA, interfering with RelA-p50 heterodimer formation in the nucleus, thereby inhibiting its DNA binding in CTLs. Thus, PPARδ is a critical regulator of CTL effector function. Significance: Here, we provide the first direct evidence that PPARδ plays a critical role in suppressing the immune response against tumors by downregulating RelA DNA-binding activity. This results in decreased expression of perforin, granzyme B, and IFNγ. Thus, PPARδ may serve as a valuable target for developing future cancer immunotherapies., (©2024 The Authors; Published by the American Association for Cancer Research.)

While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8 + T cells in vitro as compared with single EP antagonists. CD8 + T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC) min+/- spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist., Significance: Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule., (© 2023 The Authors; Published by the American Association for Cancer Research.)

Chronic inflammation is a well-established risk factor for several diseases, including cancer. It influences tumor cell biology and the type and density of immune cells in the tumor microenvironment (TME), promoting cancer development. While proinflammatory cytokines and chemokines modulate cancer development, emerging evidence has shown that prostaglandin E2 (PGE2) is a known mediator connecting chronic inflammation to cancerization. This review highlights recent advances in our understanding of how the elevation of PGE2 production promotes gastrointestinal cancer initiation, progression, invasion, metastasis, and recurrence, including modulation of immune checkpoint signaling and the type and density of immune cells in the tumor/tissue microenvironment., (©2022 American Association for Cancer Research.)

The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2-derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4-PI3K-Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4-PI3K-Akt-NFκB-PD-1 signaling pathway. In contrast, inhibiting the COX-2-PGE2-EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion., Prevention Relevance: These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs., (©2022 American Association for Cancer Research.)

The First Lady of the United States, Dr. Jill Biden, visited the Hollings Cancer Center at the Medical University of South Carolina on October 25, 2021. This Commentary remarks on the administration's goal of directing public attention to cancer screening and prevention as part of an overall effort to recover ground lost in the COVID-19 pandemic, particularly in underserved communities., (©2022 American Association for Cancer Research.)

Chronic inflammation is a known risk factor for gastrointestinal cancer. The evidence that nonsteroidal anti-inflammatory drugs suppress the incidence, growth, and metastasis of gastrointestinal cancer supports the concept that a nonsteroidal anti-inflammatory drug target, cyclooxygenase, and its downstream bioactive lipid products may provide one of the links between inflammation and cancer. Preclinical studies have demonstrated that the cyclooxygenase-2-prostaglandin E 2 pathway can promote gastrointestinal cancer development. Although the role of this pathway in cancer has been investigated extensively for 2 decades, only recent studies have described its effects on host defenses against transformed epithelial cells. Overcoming tumor-immune evasion remains one of the major challenges in cancer immunotherapy. This review summarizes the impacts of the cyclooxygenase-2-prostaglandin E 2 pathway on gastrointestinal cancer development. Our focus was to highlight recent advances in our understanding of how this pathway induces tumor immune evasion., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

On October 20, 2021, I had the privilege of testifying before the House Energy and Commerce Committee, Subcommittee on Health Hearing on Enhancing Public Health: Legislation to Protect Children and Families. This commentary is based on the written testimony I provided to the Subcommittee on issues related to cancer screening and early detection. It highlights the research progress, updated guidelines, and new challenges in this field, emphasizing the importance of screening asymptomatic, at-risk population to detect precancerous lesions or cancer at an early stage., (©2021 American Association for Cancer Research.)

PD-L1 expression is elevated in various human cancers, including colorectal cancer. High levels of PD-L1 expressed on tumor epithelial cells are one of the potential mechanisms by which tumor cells become resistant to immune attack. However, PD-L1 regulation in tumor cells is not fully understood. Here we demonstrate that mutations in the adenomatous polyposis coli (APC) gene lead to colonic epithelial cell resistance to CD8 + T cell cytotoxicity by induction of PD-L1 expression. Mechanistically, this occurs as a result of the β-catenin/TCF4 complex binding to the PD-L1 promoter, leading to increased transcription. Our findings not only reveal a novel mechanism by which APC mutations induce tumor immune evasion via an immune checkpoint pathway but also pave the way for developing β-catenin or TCF4 inhibitors as possible new options for immune checkpoint inhibition., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The Division of Cancer Prevention of the National Cancer Institute (NCI) and the Office of Disease Prevention of the National Institutes of Health co-sponsored the Translational Advances in Cancer Prevention Agent Development Meeting on August 27 to 28, 2020. The goals of this meeting were to foster the exchange of ideas and stimulate new collaborative interactions among leading cancer prevention researchers from basic and clinical research; highlight new and emerging trends in immunoprevention and chemoprevention as well as new information from clinical trials; and provide information to the extramural research community on the significant resources available from the NCI to promote prevention agent development and rapid translation to clinical trials. The meeting included two plenary talks and five sessions covering the range from pre-clinical studies with chemo/immunopreventive agents to ongoing cancer prevention clinical trials. In addition, two NCI informational sessions describing contract resources for the preclinical agent development and cooperative grants for the Cancer Prevention Clinical Trials Network were also presented., Competing Interests: CONFLICTS OF INTEREST Drs. Allen, Clapper, Dashwood, Demehri, DuBois, Johnson, Kensler, Khan, Mallery, Miller, Mohammed, Rao, Schoen, Sharp, Szabo, and You have no FCOI to declare. Dr. Brown owns stock in GeneTex, whose products are not discussed in this manuscript. Dr. Chan has previously received grant support and consulting fees from Bayer Pharma AG; consulting fees from Pfizer Inc. and Boehringer Ingelheim. Dr. Disis received grant funding from Pfizer, Precigen, Bavarian Nordisk, and Veanna; is a stockholder in Epithany; and is an inventor with patents held by the University of Washington. Dr. Glynn has received support from research grants to his employer from AstraZeneca, Kowa, and Pfizer. The Brigham & Women’s Hospital holds patents for use of inflammatory biomarkers in cardiovascular disease. The CANTOS trial was funded by Novartis. Dr. Liby is an inventor on patents for synthetic triterpenoids and rexinoids. Dr. Lipkin is PI on grant U01-CA233056 that includes work performed by Nouscom, LLC. Dr. Meuillet is a scientific co-founder and member of the Management Team of PHusis, which is developing PHT-427. Dr. Roden is a co-founder of and has an equity ownership interest in Papivax LLC. Also, he owns Papivax Biotech Inc. stock options and is a member of Papivax Biotech Inc.’s Scientific Advisory Board. Under a licensing agreement between Papivax Biotech, Inc. and the Johns Hopkins University, the University and Dr. Roden are entitled to royalties on an invention described in this article. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Dr. Siegfried has a US Patent Pending: #62650892. Dr. Shirwan is a CEO at FasCure Therapeutics, LLC, and has ownership interest (including stocks and patents) in the Company. Dr. Vilar has a consulting or advisory role with Janssen Research and Development, and Recursion Pharma., (Copyright © 2021 Korean Society of Cancer Prevention.)

The COVID-19 pandemic has had an enormous impact on our society and healthcare delivery in the United States. Importantly, elective procedures and screening exams for cancer have been delayed or canceled over the past 4-5 months raising concerns over the future incidence and outcomes for those at risk or diagnosed with cancer. It is clear to everyone in the cancer field that the earlier we detect premalignant disease or cancer, the better the clinical outcome is for the patient. Most healthcare institutions have now put safety procedures and guidelines in place, which have dramatically reduced the risk of viral spread during encounters in their healthcare facilities. We must now encourage the public and those individuals at high risk for cancer to resume normal cancer screening., (©2020 American Association for Cancer Research.)

Background & Aims: Prostaglandin E 2 (PGE 2 ) promotes colorectal tumor formation and progression by unknown mechanisms. We sought to identify microRNAs (miRNAs) that might mediate the effects of PGE 2 on colorectal cancer (CRC) development., Methods: We incubated LS174T colorectal cancer cells with PGE 2 or without (control) and used miRNA-sequencing technology to compare expression patterns of miRNAs. We knocked down levels of specific miRNAs or proteins in cells using small interfering RNAs or genome editing. Cells were analyzed by immunoblot, quantitative polymerase chain reaction, chromosome immunoprecipitation, cell invasion, and luciferase reporter assays; we measured gene expression, binding activity, cell migration and invasion, and transcriptional activity of transcription factors. NOD-scidIL-2Rg -/- mice were given injections of LS174T cells, and growth of primary tumors and numbers of liver and lung metastases were quantified and analyzed by histology. We used public databases to identify correlations in gene expression pattern with patient outcomes., Results: We identified miRNA 675-5p (miR675-5p) as the miRNA most highly up-regulated by incubation of colorectal cancer cells with PGE 2 . PGE 2 increased expression of miR675-5p by activating expression of Myc, via activation of protein kinase B, also known as (AKT), nuclear factor κB, and β-catenin. PGE 2 increased the invasive activities of cultured CRC cells. LS174T cells incubated with PGE 2 formed more liver and lung metastases in mice than control LS174T cells. We identified a 3' untranslated region in the TP53 messenger RNA that bound miR675-5p; binding resulted in loss of the p53 protein. Expression of miR675-5p or its precursor RNA, H19, correlated with expression of cyclooxygenase-1 and cyclooxygenase-2 and shorter survival times of patients with CRC., Conclusions: We found that treatment of mice with PGE 2 increased CRC cells invasive activity and ability to form liver and lung metastases. PGE 2 down-regulates expression of p53 by increasing expression of miR675-5p, which binds to and prevents translation of TP53 messenger RNA. These findings provide insight into the mechanisms by which PGE 2 promotes tumor development and progression. Strategies to target PGE 2 might be developed for treatment of CRC., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The nuclear hormone receptor peroxisome proliferator-activated receptor delta (PPARδ) is a ligand-dependent transcription factor involved in fatty acid metabolism, obesity, wound healing, inflammation, and cancer. Although PPARδ has been shown to promote intestinal adenoma formation and growth, the molecular mechanisms underlying the contribution of PPARδ to colorectal cancer remain unclear. Here, we demonstrate that activation of PPARδ induces expansion of colonic cancer stem cells (CSC) and promotes colorectal cancer liver metastasis by binding to the Nanog promoter and enhancing Nanog expression. Moreover, PPARδ mediated the effect of a high-fat diet in promoting liver metastasis and induction of colonic CSC expansion. Our findings uncover a novel role of dietary fats in colorectal cancer metastasis and reveal novel mechanisms underlying PPARδ-mediated induction of CSCs and those responsible for the contribution of dietary fats to colorectal cancer progression. These findings may provide a rationale for developing PPARδ antagonists to therapeutically target CSCs in colorectal cancer. SIGNIFICANCE: These findings show that PPARδ contributes to colorectal cancer metastasis by expanding the CSC population, indicating that antagonists that target PPARδ may be beneficial in treating colorectal cancer., (©2019 American Association for Cancer Research.)

Quantifying tumor burden is important for following the natural history of orthotopic colon cancer and therapeutic efficacy. Bioluminescence imaging (BLI) is commonly used for such assessment and has both advantages and limitations. We compared BLI and magnetic resonance imaging (MRI) for quantifying orthotopic tumors in a mouse model of colon cancer. Among sequences tested, T2-based MRI imaging ranked best overall for colon cancer border delineation, contrast, and conspicuity. Longitudinal MRI detected tumor outside the colon, indistinguished by BLI. Colon tumor weights calculated from MRI in vivo correlated highly with tumor weights measured ex vivo whereas the BLI signal intensities correlated relatively poorly and this difference in correlations was highly significant. This suggests that MRI may more accurately assess tumor burden in longitudinal monitoring of orthotopic colon cancer in this model as well as in other models.

The recent pace, extent, and impact of paradigm-changing cancer prevention science has been remarkable. The American Association for Cancer Research (AACR) convened a 3-day summit, aligned with five research priorities: (i) Precancer Atlas (PCA). (ii) Cancer interception. (iii) Obesity-cancer linkage, a global epidemic of chronic low-grade inflammation. (iv) Implementation science. (v) Cancer disparities. Aligned with these priorities, AACR co-led the Lancet Commission to formally endorse and accelerate the NCI Cancer Moonshot program, facilitating new global collaborative efforts in cancer control. The expanding scope of creative impact is perhaps most startling-from NCI-funded built environments to AACR Team Science Awarded studies of Asian cancer genomes informing global primary prevention policies; cell-free epigenetic marks identifying incipient neoplastic site; practice-changing genomic subclasses in myeloproliferative neoplasia (including germline variant tightly linked to JAK2 V617F haplotype); universal germline genetic testing for pancreatic cancer; and repurposing drugs targeting immune- and stem-cell signals (e.g., IL-1β, PD-1, RANK-L) to cancer interception. Microbiota-driven IL-17 can induce stemness and transformation in pancreatic precursors (identifying another repurposing opportunity). Notable progress also includes hosting an obesity special conference (connecting epidemiologic and molecular perspectives to inform cancer research and prevention strategies), co-leading concerted national implementation efforts in HPV vaccination, and charting the future elimination of cancer disparities by integrating new science tools, discoveries and perspectives into community-engaged research, including targeted counter attacks on e-cigarette ad exploitation of children, Hispanics and Blacks. Following this summit, two unprecedented funding initiatives were catalyzed to drive cancer prevention research: the NCI Cancer Moonshot (e.g., PCA and disparities); and the AACR-Stand Up To Cancer bold "Cancer Interception" initiative., (©2018 American Association for Cancer Research.)

Chronic inflammation is a risk factor for gastrointestinal cancer and other diseases. Most studies have focused on cytokines and chemokines as mediators connecting chronic inflammation to cancer, whereas the involvement of lipid mediators, including prostanoids, has not been extensively investigated. Prostanoids are among the earliest signaling molecules released in response to inflammation. Multiple lines of evidence suggest that prostanoids are involved in gastrointestinal cancer. In this Review, we discuss how prostanoids impact gastrointestinal cancer development. In particular, we highlight recent advances in our understanding of how prostaglandin E2 induces the immunosuppressive microenvironment in gastrointestinal cancers.

Emerging evidence suggests that the primary tumor influences the development of supportive metastatic microenvironments, referred to as premetastatic niches, in certain distant organs before arrival of metastatic cells. However, the mechanisms underlying the contributions of the primary tumor to premetastatic niche formation are not fully understood. Here, we demonstrate that colorectal carcinoma cells secrete VEGFA, which stimulates tumor-associated macrophages to produce CXCL1 in the primary tumor. Elevation of CXCL1 in premetastatic liver tissue recruited CXCR2-positive myeloid-derived suppressor cells (MDSC) to form a premetastatic niche that ultimately promoted liver metastases. Importantly, premetastatic liver-infiltrating MDSCs induced tumor cell survival without involvement of innate or adaptive immune responses. Our study provides the first evidence that primary malignant cell-secreted VEGFA stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive MDSCs to form a premetastatic niche to promote liver metastases. Our findings not only shed light on how the tumor microenvironment contributes to premetastatic niche formation at distant sites, but they also provide comprehensive insights into how MDSCs are recruited to other organs where they contribute to metastatic spread of disease. Moreover, our work also provides a rationale for development of CXCR2 antagonists to inhibit or prevent metastatic spread of disease. Cancer Res; 77(13); 3655-65. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Krüppel-like factor 12 (KLF12) is a transcription factor that plays a role in normal kidney development and repression of decidualization. KLF12 is frequently elevated in esophageal adenocarcinoma and has been reported to promote gastric cancer progression. Here, we examined the role of KLF12 in colorectal cancer (CRC). Indeed, KLF12 promotes tumor growth by directly activating early growth response protein 1 (EGR1). The levels of KLF12 and EGR1 correlate synergistically with a poor prognosis. These results indicate that KLF12 likely plays an important role in CRC and could serve as a potential prognostic marker and therapeutic target.

Tumor-associated inflammation can create an immunosuppressive microenvironment allowing tumor cells to escape immunosurveillance. Inhibiting immunosuppression remains one of the major challenges in cancer immunotherapy via checkpoint inhibitors. Recent preclinical data from the Reis e Sousa group may provide a strong rationale for developing new therapeutics to subvert tumor-induced immunosuppression via prostaglandin inhibition., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background & Aims: Inflammation may contribute to the formation, maintenance, and expansion of cancer stem cells (CSCs), which have the capacity for self-renewal, differentiation, and resistance to cytotoxic agents. We investigated the effects of the inflammatory mediator prostaglandin E2 (PGE2) on colorectal CSC development and metastasis in mice and the correlation between levels of PGE2 and CSC markers in human colorectal cancer (CRC) specimens., Methods: Colorectal carcinoma specimens and matched normal tissues were collected from patients at the Mayo Clinic (Scottsdale, AZ) and analyzed by mass spectrometry and quantitative polymerase chain reaction. Human primary CRC cells and mouse tumor cells were isolated using microbeads or flow cytometry and analyzed for sphere-formation and by flow cytometry assays. LS-174T cells were sorted by flow cytometry (for CD133(+)CD44(+) and CD133(-)CD44(-) cells) and also used in these assays. NOD-scidIL-2Rγ(-/-) (NSG) mice were given cecal or subcutaneous injections of LS-174T or human primary CRC cells. Apc(Min/+) mice and NSG mice with orthotopic cecal tumors were given vehicle (controls), PGE2, celecoxib, and/or Ono-AE3-208. PGE2 downstream signaling pathways were knocked down with small hairpin RNAs, expressed from lentiviral vectors in LS-174T cells, or blocked with inhibitors in human primary CRC cells., Results: Levels of PGE2 correlated with colonic CSC markers (CD133, CD44, LRG5, and SOX2 messenger RNAs) in human colorectal carcinoma samples. Administration of PGE2 to Apc(Min/+) mice increased tumor stem cells and tumor burden, compared with controls. NSG mice given PGE2 had increased numbers of cecal CSCs and liver metastases compared with controls after intracecal injection of LS-174T or human primary CRC cells. Alternatively, celecoxib, an inhibitor of prostaglandin-endoperoxide synthase 2, reduced polyp numbers in Apc(Min/+) mice, liver metastasis in NSG mice with orthotopic tumors, and numbers of CSCs in Apc(Min/+) and NSG mice. Inhibitors or knockdown of PGE2 receptor 4 (EP4), phosphoinositide 3-kinase (PI3K) p85α, extracellular signal-regulated kinase 1 (ERK1), or nuclear factor (NF)-κB reduced PGE2-induced sphere formation and expansion of LS-174T and/or human primary CRC cells. Knockdown of ERK1 or PI3K p85α also attenuated PGE2-induced activation of NF-κB in LS-174T cells. An EP4 antagonist reduced the ability of PGE2 to induce CSC expansion in orthotopic tumors and to accelerate the formation of liver metastases. Knockdown experiments showed that NF-κB was required for PGE2 induction of CSCs and metastasis in mice., Conclusions: PGE2 induces CSC expansion by activating NF-κB, via EP4-PI3K and EP4-mitogen-activated protein kinase signaling, and promotes the formation of liver metastases in mice. The PGE2 signaling pathway therefore might be targeted therapeutically to slow CSC expansion and colorectal cancer progression., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Chronic inflammation contributes to cancer development via multiple mechanisms. One potential mechanism is that chronic inflammation can generate an immunosuppressive microenvironment that allows advantages for tumor formation and progression. The immunosuppressive environment in certain chronic inflammatory diseases and solid cancers is characterized by accumulation of proinflammatory mediators, infiltration of immune suppressor cells and activation of immune checkpoint pathways in effector T cells. In this review, we highlight recent advances in our understanding of how immunosuppression contributes to cancer and how proinflammatory mediators induce the immunosuppressive microenvironment via induction of immunosuppressive cells and activation of immune checkpoint pathways., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)