Crosstalk between the Tumor Microenvironment and Immune System in Pancreatic Ductal Adenocarcinoma: Potential Targets for New Therapeutic Approaches

Parente, Paola; Parcesepe, Pietro; Covelli, Claudia; Olivieri, Nunzio; Remo, Andrea; Pancione, Massimo; Latiano, Tiziana Pia; Graziano, Paolo; Maiello, Evaristo; Giordano, Guido

doi:10.1155/2018/7530619

Cited by 29 publications

(26 citation statements)

References 99 publications

(120 reference statements)

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“…This paves the way to potential new therapies to replace or combine with the current standard of care. A combination of FOLFOXIRI with immunotherapy may revolutionize standard clinical care [70][71][72]. The presence of immune cells in the tumor microenvironment of mCRC after first-line chemotherapy treatment can be used to predict potential combinations with immunotherapy [72][73][74].…”

Section: Discussionmentioning

confidence: 99%

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

et al. 2020

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The combination of folinic acid, 5-fluorouracil, oxaliplatin and/or irinotecan (FOLFOXIRI) is the standard of care for metastatic colorectal cancer (CRC). This strategy inhibits tumor growth but provokes drug resistance and serious side effects. We aimed to improve FOLFOXIRI by optimization of the dosing and the sequence of drug administration. We employed an orthogonal array composite design and linear regression analysis to obtain cell line-specific drug combinations for four CRC cell lines (DLD1, SW620, HCT116, LS174T). Our results confirmed the synergy between folinic acid and 5-fluorouracil and additivity, or even antagonism, between the other drugs of the combination. The drug combination administered at clinical doses resulted in significantly higher antagonistic interactions compared to the low-dose optimized drug combination (ODC). We found that the concomitant administration of the optimized drug combination (ODC) was comparatively active to sequential administration. However, the administration of oxaliplatin or the active metabolite of irinotecan seemed to sensitize the cells to the combination of folinic acid and 5-fluorouracil. ODCs were similarly active in non-cancerous cells as compared to the clinically used doses, indicating a lack of reduction of side effects. Interestingly, ODCs were inactive in CRC cells chronically pretreated with FOLFOXIRI, suggesting the occurrence of resistance. We were unable to improve FOLFOXIRI in terms of efficacy or specificity. Improvement of CRC treatment should come from the optimization of targeted drugs and immunotherapy strategies.

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Section: Discussionmentioning

confidence: 99%

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

et al. 2020

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“…This favors cancer progression by protecting pancreatic tumors from immune surveillance as well as regional and distant metastasis [20]. Additionally, the hypoxic environment, acidic extracellular pH, and high interstitial fluid pressure in the TME also act to enhance tumorigenesis and tumor progression [21]. In order to create an environment that is conducive for tumor growth, tumor supporting cells are upregulated, whereas the immune cells are downregulated in the TME of pancreatic cancer.…”

Section: Main Textmentioning

confidence: 99%

Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment

Looi

Chung

Leong

et al. 2019

J Exp Clin Cancer Res

131

111

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Background Pancreatic cancer is one of the most lethal type of cancers, with an overall five-year survival rate of less than 5%. It is usually diagnosed at an advanced stage with limited therapeutic options. To date, no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Compared with other cancers, pancreatic cancer exhibits remarkable resistance to conventional therapy and possesses a highly immunosuppressive tumor microenvironment (TME). Main body In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME. Conclusions It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.

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“…These findings demonstrate the capacity and necessity to develop immune‐oncology methods using the organ‐on‐a‐chip platform, as immune response is a key component of the in vivo environment (evidenced by the cell–cell interactions of immune and tumor cells) . A detailed discussion on crosstalk between the TME and immune system can be found in a recent review paper …”

Section: Applications Of Cancer‐on‐a‐chip Technologiesmentioning

confidence: 81%

“…Immune system elements play a large role in the TME, with crosstalk between the immune and cellular TME components . Interactions within the TME contribute to cancer initiation (carcinogenesis), progression, and metastasis.…”

Section: Applications Of Cancer‐on‐a‐chip Technologiesmentioning

confidence: 99%

Cancer Modeling‐on‐a‐Chip with Future Artificial Intelligence Integration

Fetah

DiPardo

Kongadzem

et al. 2019

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Cancer is one of the leading causes of death worldwide, despite the large efforts to improve the understanding of cancer biology and development of treatments. The attempts to improve cancer treatment are limited by the complexity of the local milieu in which cancer cells exist. The tumor microenvironment (TME) consists of a diverse population of tumor cells and stromal cells with immune constituents, microvasculature, extracellular matrix components, and gradients of oxygen, nutrients, and growth factors. The TME is not recapitulated in traditional models used in cancer investigation, limiting the translation of preliminary findings to clinical practice. Advances in 3D cell culture, tissue engineering, and microfluidics have led to the development of “cancer‐on‐a‐chip” platforms that expand the ability to model the TME in vitro and allow for high‐throughput analysis. The advances in the development of cancer‐on‐a‐chip platforms, implications for drug development, challenges to leveraging this technology for improved cancer treatment, and future integration with artificial intelligence for improved predictive drug screening models are discussed.

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Crosstalk between the Tumor Microenvironment and Immune System in Pancreatic Ductal Adenocarcinoma: Potential Targets for New Therapeutic Approaches

Cited by 29 publications

References 99 publications

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

Drug-Drug Interactions of Irinotecan, 5-Fluorouracil, Folinic Acid and Oxaliplatin and Its Activity in Colorectal Carcinoma Treatment

Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment

Cancer Modeling‐on‐a‐Chip with Future Artificial Intelligence Integration

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