An easily adopted murine model of distal pancreatectomy for investigating immunotherapy efficacy in resectable pancreatic adenocarcinoma

AbstractBackgroundAlthough surgery provides the greatest therapeutic benefit to eligible pancreatic ductal adenocarcinoma (PDAC) patients it does not significantly improve survival for the majority of patients. Unfortunately our understanding of the therapeutic benefit of combining surgery with different treatment modalities including promising immunotherapeutics is limited by the current lack of easily adopted surgical models. The purpose of this study was to develop a surgically resectable model of PDAC in immunocompetent mice for use in preclinical investigations.Materials and MethodsSurgically resectable orthotopic tumors were generated by injecting Pan02 cells into the tail of the pancreas. Fifteen days post implantation the primary tumors and tail of the pancreas were resected by laparotomy while preserving the spleen. Splenic function, tumor growth, immune phenotyping and survival were assessed following surgical resection of the primary tumor mass.ResultsAs expected orthotopic tumor implants recapitulated many of the major histological hallmarks of PDAC including disrupted lobular structure and vascular invasion. Preservation of splenic immune cell viability and function was not associated with improved survival following surgery alone. However, pre-operative vaccination with GVAX was associated with improved survival which was not impacted by surgery.ConclusionThis represents the first murine model of surgically resectable murine model of PDAC which recapitulates known pathological hallmarks of human disease in an immune competent model while allowing spleen preservation. This relatively simple and easily adopted approach provides an ideal platform to examine the efficacy of potential immunotherapy combinations for PDAC surgery patients.

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A novel 20-gene prognostic score in pancreatic adenocarcinoma

10.21203/rs.2.15410/v1 ◽

2019 ◽

Author(s):

Secil Demirkol Canli ◽

Ege Dedeoglu ◽

Muhammad Waqas Akbar ◽

Baris Kucukkaraduman ◽

Murat Isbilen ◽

...

Keyword(s):

Immune Cell ◽

Prognostic Score ◽

Performance Status ◽

Cyclin B1 ◽

Pancreatic Tissue ◽

Tnm Staging ◽

Prognostic Indicators ◽

Ductal Adenocarcinoma ◽

Primary Tumors ◽

And Performance

Abstract Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Known risk factors for this disease are currently insufficient in predicting mortality. The only FDA approved prognostic biomarker for PDAC patients is CA19-9. This, along with AJCC TNM staging and performance status, are considered important prognostic indicators in clinical practice. In order to better prognosticate patients with PDAC, we identified a novel panel of genes by utilizing publically available microarray and RNAseq data of PDAC tumors from GEO and TCGA. Expression of 20 genes were significantly associated with overall survival in four datasets and event-free survival in TCGA. A score generated based on the expression matrix of these genes could be validated in two independent cohorts. We find that this “Pancreatic cancer prognostic score 20 – PPS20” is dramatically elevated in metastatic tissue compared to primary tumor, and is higher in primary tumors compared to normal pancreatic tissue. Transcriptomic analyses show that tumors with low PPS20 have overall more immune cell infiltration and a higher CD8 T cell/Treg ratio when compared to those with high PPS20. Analyses of proteomic data from TCGA PAAD indicated higher levels of Cyclin B1, RAD51, EGFR and a lower E-cadherin/Fibronectin ratio in tumors with high PPS20. The PPS20 score defines not only prognostic and biological sub-groups but can predict response to targeted therapy options as well. Overall, PPS20 is a stronger and more robust transcriptomic signature when compared to similar, previously published gene lists.

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Medical management of brain metastases

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa015 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Adam Lauko ◽

Yasmeen Rauf ◽

Manmeet S Ahluwalia

Keyword(s):

Brain Metastases ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Tumor Biology ◽

Therapeutic Benefit ◽

Treatment Modalities ◽

Primary Tumors ◽

Mortality And Morbidity ◽

Novel Approaches ◽

Neurocognitive Decline

Absrtract The development of brain metastases occurs in 10–20% of all patients with cancer. Brain metastases portend poor survival and contribute to increased cancer mortality and morbidity. Despite multimodal treatment options, which include surgery, radiotherapy, and chemotherapy, 5-year survival remains low. Besides, our current treatment modalities can have significant neurological comorbidities, which result in neurocognitive decline and a decrease in a patient’s quality of life. However, innovations in technology, improved understanding of tumor biology, and new therapeutic options have led to improved patient care. Novel approaches in radiotherapy are minimizing the neurocognitive decline while providing the same therapeutic benefit. In addition, advances in targeted therapies and immune checkpoint inhibitors are redefining the management of lung and melanoma brain metastases. Similar approaches to brain metastases from other primary tumors promise to lead to new and effective therapies. We are beginning to understand the appropriate combination of these novel approaches with our traditional treatment options. As advances in basic and translational science and innovative technologies enter clinical practice, the prognosis of patients with brain metastases will continue to improve.

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High CXCR4 expression in pancreatic ductal adenocarcinoma as characterized by an inflammatory tumor phenotype with potential implications for an immunotherapeutic approach.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4021 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4021-4021

Author(s):

Andreas Seeber ◽

Florian Kocher ◽

Andreas Pircher ◽

Alberto Puccini ◽

Yasmine Baca ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Immune Cell ◽

Tumor Regression ◽

Signal Transduction Pathway ◽

Cxcr4 Expression ◽

Ductal Adenocarcinoma ◽

Rna Expression ◽

Primary Tumors ◽

Pathway Gene ◽

Molecular Landscape

4021 Background: Immunotherapy is considered ineffective in the majority of patients with pancreatic ductal adenocarcinoma (PDAC), a consequence of a highly immunosuppressive tumor microenvironment (TME). However, treatment induced inhibition of CXC chemokine receptor 4 (CXCR4) and programmed cell death protein-1 (PD-1) in the COMBAT trial caused T cell infiltration and tumor regression in a subset of PDAC patients. Elucidating a phenotype that predicts response is clinically relevant. We performed a comprehensive molecular landscape study in PDAC evaluating CXCR4 RNA expression. Methods: 3,647 PDAC specimens were centrally analysed. NextGen DNA sequencing (NextSeq, 592 gene panel or NovaSeq, whole-exome sequencing), whole-transcriptome RNA sequencing (NovaSeq) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ) were performed. Gene expression is reported as TPM (Transcripts per million). Pathway gene enrichment analyses were done using GSEA (Subramaniam 2015, PNAS). Immune cell fraction was calculated by QuantiSeq (Finotello 2019, Genome Medicine). The cohort was stratified in quartiles according to CXCR4 RNA expression status. Results: Overall, CXCR4 expression was higher in primary tumors compared to distant metastasis (38 vs. 28 TPM, p < 0.0001). CXCR4-high (top quartile: > 59 TPMs), when compared to CXCR4-low (bottom quartile: < 17 TPM) PDACs, were characterized by a high prevalence of mutations in signal transduction pathway genes (e.g. GNAS: 3.6 vs. 0.5%), an increased infiltration of immune cells (e.g. CD8+ T cells, M1 macrophages), and a higher expression of HLA-DRA and HLA-E (all p < 0.0001). We detected an upregulation of CXCL9, CXCL10, CXCL12, CCL5, IDO1 and LAG3 in CXCR4-high compared to CXCR4-low tumors. In contrast, lower PD-L1 expression (17.4 vs. 13.1%, p = 0.02), genomic loss of heterozygosity (17.4 vs. 10.8%), and a lower frequency of gene amplifications in ERBB2 (2.1 vs. 0.1%), TNFRSF14 (2.0 vs. 0.1%), and TP53 (82 vs. 73%, all p < 0.0001) were observed. Moreover, CXCR4-high expression was associated with a better survival (HR: 1.417, 95% CI [1.168-1.72], p < 0.001). Conclusions: This is the first study comprehensively investigating the molecular landscape of PDACs according to CXCR4 RNA expression. High CXCR4 expression is associated with an improved survival and a pro-inflammatory phenotype that may identify a subset of tumors with greater responsiveness to immunotherapeutic approaches.

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Modulation of the Vascular-Immune Environment in Metastatic Cancer

Cancers ◽

10.3390/cancers13040810 ◽

2021 ◽

Vol 13 (4) ◽

pp. 810

Author(s):

Bo He ◽

Ruth Ganss

Keyword(s):

Immune Cell ◽

Synergistic Effects ◽

Metastatic Cancer ◽

Resistance Mechanisms ◽

Cell Trafficking ◽

Primary Tumors ◽

Adaptive Resistance ◽

Immune Therapies ◽

Approved Drugs ◽

And Function

Advanced metastatic cancer is rarely curable. While immunotherapy has changed the oncological landscape profoundly, cure in metastatic disease remains the exception. Tumor blood vessels are crucial regulators of tumor perfusion, immune cell influx and metastatic dissemination. Indeed, vascular hyperpermeability is a key feature of primary tumors, the pre-metastatic niche in host tissue and overt metastases at secondary sites. Combining anti-angiogenesis and immune therapies may therefore unlock synergistic effects by inducing a stabilized vascular network permissive for effector T cell trafficking and function. However, anti-angiogenesis therapies, as currently applied, are hampered by intrinsic or adaptive resistance mechanisms at primary and distant tumor sites. In particular, heterogeneous vascular and immune environments which can arise in metastatic lesions of the same individual pose significant challenges for currently approved drugs. Thus, more consideration needs to be given to tailoring new combinations of vascular and immunotherapies, including dosage and timing regimens to specific disease microenvironments.

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After Nf1 loss in Schwann cells, inflammation drives neurofibroma formation

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz045 ◽

2019 ◽

Vol 2 (Supplement_1) ◽

pp. i23-i32 ◽

Cited By ~ 1

Author(s):

Jonathan S Fletcher ◽

Jay Pundavela ◽

Nancy Ratner

Keyword(s):

Mast Cells ◽

Peripheral Nerve ◽

Immune Cell ◽

Neurofibromatosis Type ◽

Therapeutic Benefit ◽

Allelic Loss ◽

Type I ◽

Stat3 Signaling ◽

Patient Morbidity ◽

And Function

Abstract Plexiform neurofibromas (PNF) are peripheral nerve tumors caused by bi-allelic loss of NF1 in the Schwann cell (SC) lineage. PNF are common in individuals with Neurofibromatosis type I (NF1) and can cause significant patient morbidity, spurring research into potential therapies. Immune cells are rare in peripheral nerve, whereas in PNF 30% of the cells are monocytes/macrophages. Mast cells, T cells, and dendritic cells (DCs) are also present. NF1 mutant neurofibroma SCs with elevated Ras-GTP signaling resemble injury-induced repair SCs, in producing growth factors and cytokines not normally present in SCs. This provides a cytokine-rich environment facilitating PNF immune cell recruitment and fibrosis. We propose a model based on genetic and pharmacologic evidence in which, after loss of Nf1 in the SC lineage, a lag occurs. Then, mast cells and macrophages are recruited to nerve. Later, T cell/DC recruitment through CXCL10/CXCR3 drives neurofibroma initiation and sustains PNF macrophages and tumor growth. Stat3 signaling is an additional critical mediator of neurofibroma initiation, cytokine production, and PNF growth. At each stage of PNF development therapeutic benefit should be achievable through pharmacologic modulation of leukocyte recruitment and function.

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Profiling the intratumoral immune landscapes of primary and syngeneic Kras-driven sarcoma mouse models

10.1101/2020.07.01.181263 ◽

2020 ◽

Author(s):

Wade R. Gutierrez ◽

Amanda Scherer ◽

Gavin R. McGivney ◽

Vickie Knepper-Adrian ◽

Emily A. Laverty ◽

...

Keyword(s):

T Cell ◽

Mouse Models ◽

Primary Tumor ◽

Immune Cell ◽

Genetically Engineered ◽

Cell Transplant ◽

Tumor Models ◽

Primary Tumors ◽

Cell Composition ◽

Immunocompetent Mice

ABSTRACTThe introduction of immunotherapy has revolutionized cancer treatment and fueled interest in the immune cell composition of preclinical tumor models. Both genetically-engineered mouse models and syngeneic cell transplant approaches use immunocompetent mice to study mechanisms driving immunotherapy response and resistance. Due to their rapid and reproducible nature, there has been an expanded interest in developing new syngeneic tools from established primary tumor models. However, there are few analyses directly comparing the immune profiles of primary models with their derived syngeneic counterparts. Here we report comprehensive immunophenotyping of primary tumors from two well-established sarcoma models and four syngeneic allografts derived from these models. We observed that cell lines derived from the same type of genetically engineered primary tumor form allografts with significantly different levels of immune infiltration and intratumoral immune cell composition. Most notable are the differences in the T cell compartment of the syngeneic models, including CD4+ T cell, CD8+ T cell, and regulatory T cell populations – each of which have well-documented roles in tumor response to immunotherapy. Our findings highlight the importance of thorough characterization of syngeneic models prior to their use in preclinical studies in order to maintain scientific rigor and to increase the translatability of findings from bench to bedside.

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Maternal High-Fat Diet Persistently Alters Bone Marrow Immune Cell Proportions and Function in a Nonhuman Primate Model

Diabetes ◽

10.2337/db18-222-or ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 222-OR

Author(s):

MICHAEL J. NASH ◽

TAYLOR K. SODERBORG ◽

RACHEL C. JANSSEN ◽

ERIC M. PIETRAS ◽

JACOB E. FRIEDMAN

Keyword(s):

Bone Marrow ◽

Nonhuman Primate ◽

High Fat Diet ◽

Immune Cell ◽

High Fat ◽

Nonhuman Primate Model ◽

Primate Model ◽

And Function

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Recent Advances of Small Molecular Regulators Targeting G Protein- Coupled Receptors Family for Oncology Immunotherapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190628115644 ◽

2019 ◽

Vol 19 (16) ◽

pp. 1464-1483 ◽

Cited By ~ 2

Author(s):

Peng He ◽

Wenbo Zhou ◽

Mingyao Liu ◽

Yihua Chen

Keyword(s):

G Protein ◽

Cell Biology ◽

Immune Cell ◽

G Protein Coupled Receptors ◽

Treatment Modalities ◽

Immune Checkpoints ◽

Considerable Proportion ◽

Prostaglandin E ◽

Recent Advances ◽

G Protein Coupled

The great clinical success of chimeric antigen receptor T cell (CAR-T) and PD-1/PDL-1 inhibitor therapies suggests the drawing of a cancer immunotherapy age. However, a considerable proportion of cancer patients currently receive little benefit from these treatment modalities, indicating that multiple immunosuppressive mechanisms exist in the tumor microenvironment. In this review, we mainly discuss recent advances in small molecular regulators targeting G Protein-Coupled Receptors (GPCRs) that are associated with oncology immunomodulation, including chemokine receptors, purinergic receptors, prostaglandin E receptor EP4 and opioid receptors. Moreover, we outline how they affect tumor immunity and neoplasia by regulating immune cell recruitment and modulating tumor stromal cell biology. We also summarize the data from recent clinical advances in small molecular regulators targeting these GPCRs, in combination with immune checkpoints blockers, such as PD-1/PDL-1 and CTLA4 inhibitors, for cancer treatments.

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Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

Applied Sciences ◽

10.3390/app9224784 ◽

2019 ◽

Vol 9 (22) ◽

pp. 4784

Author(s):

Vietsch ◽

Peran ◽

Suker ◽

van den Bosch ◽

Sijde ◽

...

Keyword(s):

Cancer Progression ◽

B Lymphocyte ◽

Immune Cell ◽

Tumor Resection ◽

Progression Free Survival ◽

Tumor Stroma ◽

Recurrence Risk ◽

High Serum ◽

Ductal Adenocarcinoma ◽

Before And After

Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic KrasG12D/+; Trp53R172H/+; P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated ≥3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.

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Data Driven Mathematical Model of FOLFIRI Treatment for Colon Cancer

Cancers ◽

10.3390/cancers13112632 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2632

Author(s):

Aparajita Budithi ◽

Sumeyye Su ◽

Arkadz Kirshtein ◽

Leili Shahriyari

Keyword(s):

Mathematical Model ◽

Colon Cancer ◽

Cancer Patients ◽

Immune Cell ◽

Treatment Options ◽

Data Driven ◽

T Helper ◽

Primary Tumors ◽

Cell Fractions

Many colon cancer patients show resistance to their treatments. Therefore, it is important to consider unique characteristic of each tumor to find the best treatment options for each patient. In this study, we develop a data driven mathematical model for interaction between the tumor microenvironment and FOLFIRI drug agents in colon cancer. Patients are divided into five distinct clusters based on their estimated immune cell fractions obtained from their primary tumors’ gene expression data. We then analyze the effects of drugs on cancer cells and immune cells in each group, and we observe different responses to the FOLFIRI drugs between patients in different immune groups. For instance, patients in cluster 3 with the highest T-reg/T-helper ratio respond better to the FOLFIRI treatment, while patients in cluster 2 with the lowest T-reg/T-helper ratio resist the treatment. Moreover, we use ROC curve to validate the model using the tumor status of the patients at their follow up, and the model predicts well for the earlier follow up days.

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