Systemic Immune Activity Predicts Overall Survival in Treatment-Naïve Patients with Metastatic Pancreatic Cancer

Farren, Matthew R.; Mace, Thomas A.; Geyer, Susan; Mikhail, Sameh; Wu, Christina; Ciombor, Kristen K.; Tahiri, Sanaa; Ahn, Daniel H.; Noonan, Anne; Villalona‐Calero, Miguel A.; Bekaii‐Saab, Tanios; Lesinski, Gregory B.

doi:10.1158/1078-0432.ccr-15-1732

Cited by 90 publications

(97 citation statements)

References 48 publications

(56 reference statements)

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“…[33] Plasma was isolated from peripheral venous blood which was obtained in sodium heparin tubes from a cohort of treatment naïve patients with metastatic pancreatic cancer under an IRB approved protocol [34]. …”

Section: Methodsmentioning

confidence: 99%

Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment

et al. 2017

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Lipocalin-2 (LCN2) promotes malignant development in many cancer types. LCN2 is upregulated in patients with pancreatic ductal adenocarcinoma (PDAC) and in obese individuals, but whether it contributes to PDAC development is unclear. In this study, we investigated the effects of Lcn2 depletion on diet-induced obesity, inflammation and PDAC development. Mice with acinar cell-specific expression of KrasG12D were crossed with Lcn2-depleted animals and fed isocaloric diets with varying amounts of fat content. Pancreas were collected and analyzed for inflammation, pancreatic intraepithelial neoplasia (PanIN) and PDAC. We also used a syngeneic orthotopic PDAC mouse model to study tumor growth in the presence or absence of Lcn2 expression. In addition, to understand the mechanistic role of how LCN2 could be mediating PDAC, we studied LCN2 and its specific receptor solute carrier family 22 member 17 (SLC22A17) in human pancreatic cancer stellate cells (PSC), key mediators of the PDAC stroma. Depletion of Lcn2 diminished extracellular matrix deposition, immune cell infiltration, PanIN formation and tumor growth. Notably, it also increased survival in both obesity-driven and syngeneic orthotopic PDAC mouse models. LCN2 modulated the secretion of pro-inflammatory cytokines in PSC of the PDAC tumor microenvironment, while downregulation of LCN2-specific receptor SLC22A17 blocked these effects. Our results reveal how LCN2 acts in the tumor microenvironment links obesity, inflammation and PDAC development.

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Section: Methodsmentioning

confidence: 99%

Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment

et al. 2017

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“…Blocking of TIM3 would thus reduce the Treg mediated suppression of (tumor-specific) CTLs and allow them to target the tumor. However, the degree to which such an effect might be offset by TIM3 expression on CD4+ [81] and CD8+ [82] effector T cells remains to be determined, particularly as TIM3 expression was also associated with improved survival under certain conditions [83]. Clearly, a systematic serial analysis of changes in the expression profiles of immunodulatory molecules during immunoediting in carcinogenesis, progression of disease as well as during (effective) treatment needs to be carried out in individual tumor entities in order to dissect optimal time points and types of immunologic interventions.…”

Section: Synergistic Immunotherapeutic Opportunitiesmentioning

confidence: 99%

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

et al. 2017

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In favor of their outgrowth, cancer cells must resist immune surveillance and edit the immune response. Cancer immunoediting is characterized by fundamental changes in the cellular composition and the inflammatory cytokine profiles in the microenvironment of the primary tumor and metastatic niches, with an ever increasing complexity of interactions between tumor cells and the immune system. Recent data suggest that genetic instability and immunoediting are not necessarily disparate processes. Increasing mutational load may be associated with multiple neoepitopes expressed by the tumor cells and thus increased chances for the immune system to recognize and combat these cells. At the same time the immune system is more and more suppressed and exhausted by this process. Consequently, immune checkpoint modulation may have the potential to be most successful in genetically highly altered and usually extremely unfavorable types of cancer. Moreover, the fact that epitopes recognized by the immune system are preferentially encoded by passenger gene mutations opens windows of synergy in targeting cancer-specific signaling pathways by small molecules simultaneously with antibodies modifying T-cell activation or exhaustion.This review covers some aspects of the current understanding of the immunological basis necessary to understand the rapidly developing therapeutic endeavours in cancer treatment, the clinical achievements made, and raises some burning questions for translational research in this field.

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“…TAM) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. TAM promote tumor progression by suppressing an anti-tumor immune response, stimulating vascularization, invasion, metastasis, and increasing the tumorigenicity of cancer stem cells [14-18]. Approximately 80% of tumors have shown a positive correlation between the poor prognosis and TAM, while only tumors less than 10% of TAM density demonstrated good prognosis [19].…”

Section: Tam and Prognosis In Pancreatic Cancermentioning

confidence: 99%

Targeting tumor-associated macrophages to combat pancreatic cancer

et al. 2016

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The tumor microenvironment is replete with cells that evolve with and provide support to tumor cells during the transition to malignancy. The hijacking of the immune system in the pancreatic tumor microenvironment is suggested to contribute to the failure to date to produce significant improvements in pancreatic cancer survival by various chemotherapeutics. Regulatory T cells, myeloid derived suppressor cells, and fibroblasts, all of which constitute a complex ecology microenvironment, can suppress CD8+ T cells and NK cells, thus inhibiting effector immune responses. Tumor-associated macrophages (TAM) are versatile immune cells that can express different functional programs in response to stimuli in tumor microenvironment at different stages of pancreatic cancer development. TAM have been implicated in suppression of anti-tumorigenic immune responses, promotion of cancer cell proliferation, stimulation of tumor angiogenesis and extracellular matrix breakdown, and subsequent enhancement of tumor invasion and metastasis. Many emerging agents that have demonstrated efficacy in combating other types of tumors via modulation of macrophages in tumor microenvironments are, however, only marginally studied for pancreatic cancer prevention and treatment. A better understanding of the paradoxical roles of TAM in pancreatic cancer may pave the way to novel preventive and therapeutic approaches. Here we give an overview of the recruitment and differentiation of macrophages, TAM and pancreatic cancer progression and prognosis, as well as the potential preventive and therapeutic targets that interact with TAM for pancreatic cancer prevention and treatment.

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Systemic Immune Activity Predicts Overall Survival in Treatment-Naïve Patients with Metastatic Pancreatic Cancer

Cited by 90 publications

References 48 publications

Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment

Lipocalin-2 Promotes Pancreatic Ductal Adenocarcinoma by Regulating Inflammation in the Tumor Microenvironment

Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation

Targeting tumor-associated macrophages to combat pancreatic cancer

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