Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model

2020 ◽  
Author(s):  
Shuyang S. Qin ◽  
Booyeon J. Han ◽  
Alyssa Williams ◽  
Katherine M. Jackson ◽  
Rachel Jewell ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Tumor Immunity ◽  
Poor Prognosis ◽  
Simultaneous Presence ◽  
Preclinical Models ◽  
Tumor Microenvironments ◽  
Melanoma Model ◽  
Unique Approach ◽  
Therapeutic Responses ◽  
Systemic Immunotherapy

AbstractSynchronous metastatic melanoma, clinically defined as multiple lesions diagnosed within 6 months, has a poor prognosis. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond or exhibit lesion-specific responses. While intertumoral heterogeneity has been clinically associated with lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates clinical intertumoral heterogeneity. We show that genetic differences between tumors generate distinct tumor immune microenvironments (TIME). These TIMEs can independently upregulate PD-1/PD-L1 expression in response to ongoing anti-tumor immunity and the presence of interferon-gamma. The simultaneous presence of multiple tumors can additionally alter the TIME of each tumor. As such, our model provides a unique approach to investigate the effects of intertumoral heterogeneity on mechanisms of immunotherapy resistance.

scholarly journals Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2293
Author(s):  
Shuyang S. Qin ◽  
Booyeon J. Han ◽  
Alyssa Williams ◽  
Katherine M. Jackson ◽  
Rachel Jewell ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Immune Status ◽  
Tumor Microenvironments ◽  
Mechanistic Insight ◽  
Melanoma Model ◽  
Melanoma Patients ◽  
Selection For ◽  
Cell Death Protein ◽  
Insight Into ◽  
Systemic Immunotherapy

Metastatic melanoma portends a poor prognosis and patients may present with multiple, simultaneous tumors. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond, or exhibit lesion-specific responses wherein some metastases respond as others progress within the same patient. While intertumoral heterogeneity has been clinically associated with these mixed lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates this intertumoral genetic and microenvironmental heterogeneity. We show that genetic differences between tumors are sufficient to generate distinct tumor immune microenvironments (TIME) simultaneously in the same mouse. Furthermore, these TIMEs lead to the independent regulation of PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), a popular axis targeted by immune checkpoint therapy, in response to ongoing anti-tumor immunity and the presence of interferon-gamma. Currently, therapeutic selection for metastatic melanoma patients is guided by a single biopsy, which may not represent the immune status of all tumors. As a result, patients can display heterogeneous lesion-specific responses. Further investigations into this synchronous melanoma model will provide mechanistic insight into the effects of intertumoral heterogeneity and guide therapeutic selection in this challenging patient population.

scholarly journals Pseudomonas Exotoxin Immunotoxins and Anti-Tumor Immunity: From Observations at the Patient’s Bedside to Evaluation in Preclinical Models

Toxins ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 20 ◽  
Author(s):  
Yasmin Leshem ◽  
Ira Pastan
Keyword(s):  
Clinical Trials ◽  
Tumor Immunity ◽  
Murine Models ◽  
Preclinical Models ◽  
Pseudomonas Exotoxin ◽  
Blocking Antibody ◽  
Pseudomonas Exotoxin A ◽  
Protein Toxin ◽  
Clinical Responses ◽  
Anti Tumor Activity

Immunotoxins are protein drugs composed of a targeting domain genetically fused to a protein toxin. One killing domain being explored is a truncated Pseudomonas exotoxin A (PE). PE based immunotoxins are designed to kill cells directly by inhibiting their ability to synthesize proteins. However, observations from clinical trials suggest that this alone cannot explain their anti-tumor activity. Here we discuss patterns of clinical responses suggesting that PE immunotoxins can provoke anti-tumor immunity, and review murine models that further support this ability. In addition, we describe our preclinical effort to develop a combination therapy of local PE immunotoxins with a systemic anti-CTLA-4 immune check point blocking antibody. The combination eradicated murine tumors and prolonged the survival of mice. Clinical trials that test the ability of immunotoxins to augment immunotherapy have been recently opened.

Abstract 4055: Immune checkpoint DNA vaccines enhance anti-tumor immunity in murine melanoma model

2020 ◽  
Author(s):  
Keng-Hsueh Lan ◽  
Raghava Sriramaneni ◽  
Justin C. Jagodinsky ◽  
Claire Baniel ◽  
Amy Erbe-Gurel ◽  
...  
Keyword(s):  
Tumor Immunity ◽  
Immune Checkpoint ◽  
Dna Vaccines ◽  
Murine Melanoma ◽  
Melanoma Model

scholarly journals Decreased ex vivo production of interferon-gamma is associated with severity and poor prognosis in patients with lupus

2017 ◽  
Vol 19 (1) ◽  
Author(s):  
Sung Soo Ahn ◽  
Eun Seong Park ◽  
Joo Sung Shim ◽  
Sang-Jun Ha ◽  
Beom Seok Kim ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Poor Prognosis ◽  
Ex Vivo

The impact of sidedness of colorectal cancer in tumor immunity.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 584-584
Author(s):  
Masaaki Nishi ◽  
Mitsuo Shimada ◽  
Hideya Kashihara ◽  
Jun Higashijima ◽  
Kozo Yoshikawa ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factors ◽  
Tumor Immunity ◽  
Poor Prognosis ◽  
Molecular Characteristics ◽  
Clinicopathological Factors ◽  
Significant Difference ◽  
Relationship Of ◽  
The Impact ◽  
The Relationship

584 Background: Clinical and molecular characteristics are different between Right-side and left-sided colorectal cancer (CRC). The aim of this study was to clarify the significance of the correlation of the Sidedness of CRC and tumor immunity. Methods: A total of 116 patients who underwent curative colectomy for stage II/III CRC were included in this study. The expression of PD-1, PD-L1, FoxP3, TGF-b, and IDO was examined by immunohistochemistry and the relationship of sidedness to several prognostic factors was examined. Results: In clinicopathological factors, there were no significant difference between right sided and left sided CRC except for differentiation. Regarding tumor immunity, there were no significant difference in PD-1 and IDO expression. However, Fox P3 (right side 72% vs. left side 59%) and TGFβ (right side 72% vs. left side 57%) tended to be highly expressed in right side(p < 0.1). PDL1 was significantly highly expressed in right side(right side 65% vs. left side 35%, p < 0.05). In OS and DFS, the patients with right sided tumor tended to have poor prognosis compared with left side (p < 0.1). The PD-L1 positive patients of right-sided tumor had poor prognosis (p < 0.05). Conclusions: Sidedness is associated with tumor immunity in colorectal cancer.

scholarly journals Mesenchymal tumor organoid models recapitulate rhabdomyosarcoma subtypes

2022 ◽  
Author(s):  
Michael T. Meister ◽  
Marian J. A. Groot Koerkamp ◽  
Terezinha de Souza ◽  
Willemijn B. Breunis ◽  
Ewa Frazer-Mendelewska ◽  
...  
Keyword(s):  
Drug Screening ◽  
Poor Prognosis ◽  
Drug Sensitivity ◽  
Molecular Genetic ◽  
Soft Tissue Sarcomas ◽  
Preclinical Models ◽  
Replicative Stress ◽  
Risk Patients ◽  
Research Questions ◽  
Aggressive Tumors

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here we describe the generation of a collection of pediatric RMS tumor organoid (tumoroid) models comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within four to eight weeks, indicating the feasibility of personalized drug screening. Molecular, genetic and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to six months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.

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