scholarly journals The KrasG12D;Trp53fl/fl murine model of undifferentiated pleomorphic sarcoma is macrophage dense, lymphocyte poor, and resistant to immune checkpoint blockade

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0253864
Author(s):  
Karys M. Hildebrand ◽  
Arvind K. Singla ◽  
Reid McNeil ◽  
Kayla L. Marritt ◽  
Kurt N. Hildebrand ◽  
...  
Keyword(s):  
Soft Tissue Sarcomas ◽  
Rapid Onset ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Pleomorphic Sarcoma ◽  
Hindlimb Muscles ◽  
Improved Outcomes ◽  
Lymphocytic Infiltrates ◽  
Infiltrating Lymphocytes

Sarcomas are rare, difficult to treat, mesenchymal lineage tumours that affect children and adults. Immunologically-based therapies have improved outcomes for numerous adult cancers, however, these therapeutic strategies have been minimally effective in sarcoma so far. Clinically relevant, immunologically-competent, and transplantable pre-clinical sarcoma models are essential to advance sarcoma immunology research. Herein we show that Cre-mediated activation of KrasG12D, and deletion of Trp53, in the hindlimb muscles of C57Bl/6 mice results in the highly penetrant, rapid onset undifferentiated pleomorphic sarcomas (UPS), one of the most common human sarcoma subtypes. Cell lines derived from spontaneous UPS tumours can be reproducibly transplanted into the hindlimbs or lungs of naïve, immune competent syngeneic mice. Immunological characterization of both spontaneous and transplanted UPS tumours demonstrates an immunologically-‘quiescent’ microenvironment, characterized by a paucity of lymphocytes, limited spontaneous adaptive immune pathways, and dense macrophage infiltrates. Macrophages are the dominant immune population in both spontaneous and transplanted UPS tumours, although compared to spontaneous tumours, transplanted tumours demonstrate increased spontaneous lymphocytic infiltrates. The growth of transplanted UPS tumours is unaffected by host lymphocyte deficiency, and despite strong expression of PD-1 on tumour infiltrating lymphocytes, tumours are resistant to immunological checkpoint blockade. This spontaneous and transplantable immune competent UPS model will be an important experimental tool in the pre-clinical development and evaluation of novel immunotherapeutic approaches for immunologically cold soft tissue sarcomas.

scholarly journals P2.04-20 Immunologic Characterization of Fibrinous Pericarditis as an Immune Checkpoint Blockade Toxicity in NSCLC

2018 ◽  
Vol 13 (10) ◽  
pp. S738
Author(s):  
M. Altan ◽  
M. Toki ◽  
D. Carvajal-Hausdorf ◽  
S. Gettinger ◽  
R. Herbst ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

Abstract 870: Derivation and characterization of antibodies from immune checkpoint blockade treated cancer patients

2016 ◽  
Author(s):  
Mark Branum ◽  
Laura Smith ◽  
Heather Brett ◽  
Paul Algate ◽  
Brad Greenfield ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Immune Checkpoint Blockade to Improve Tumor Infiltrating Lymphocytes for Adoptive Cell Therapy

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0153053 ◽  
Author(s):  
Krithika N. Kodumudi ◽  
Jessica Siegel ◽  
Amy M. Weber ◽  
Ellen Scott ◽  
Amod A. Sarnaik ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Immune Checkpoint ◽  
Adoptive Cell Therapy ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Infiltrating Lymphocytes

scholarly journals Characterization of genetics in patients with mucosal melanoma treated with immune checkpoint blockade

2021 ◽  
Author(s):  
Elizabeth I. Buchbinder ◽  
Jason L. Weirather ◽  
Michael Manos ◽  
Brian J. Quattrochi ◽  
Lynette M. Sholl ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Mucosal Melanoma ◽  
Checkpoint Blockade

scholarly journals Hiding in the dark: pan-cancer characterization of expression and clinical relevance of CD40 to immune checkpoint blockade therapy

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Chi Yan ◽  
Ann Richmond
Keyword(s):  
Immune Checkpoint ◽  
Tumor Response ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I ◽  
List Type ◽  
Cancer Types ◽  
Pan Cancer ◽  
Cancer Bioinformatics

Highlights CD40 expression correlates with the type I anti-tumor response and better survival. Pan-cancer bioinformatics characterization reveals reduced CD40 expression in 11 cancer types, including RASmut melanoma compared to nevi. RAS mutation correlates with reduced CD40 expression in malignant melanoma. CD40 expression is associated with better response to immune checkpoint blockade therapy in melanoma.

scholarly journals BRAF-MEK inhibitors as steroid-sparing bridge prior to checkpoint blockade therapy in symptomatic intracranial melanoma

2021 ◽  
pp. MMT55
Author(s):  
Karam Khaddour ◽  
Tanner M Johanns ◽  
George Ansstas
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
High Dose ◽  
High Efficacy ◽  
Mek Inhibitors ◽  
Best Management ◽  
Improved Outcomes ◽  
Braf Mutant ◽  
Steroid Sparing

The introduction of immune checkpoint blockade (ICB) and BRAF-MEK inhibitors has substantially improved outcomes in patients with metastatic melanoma. However, several challenging factors may hinder the efficacy of ICB in patients with symptomatic intracranial metastatic melanoma who are immunosuppressed due to the use of steroids prior to the administration of ICB. This has resulted in the exclusion of patients treated with high dose steroid at baseline from the majority of ICB clinical trials. In addition, despite the high efficacy of BRAF-MEK inhibitors in BRAF-mutant intracranial metastatic melanoma, most tumors will eventually progress. This demonstrates a gap in addressing the best management in such patients. Here, we present a case demonstrating our approach in this patient population.

scholarly journals Current status of PD-1/PD-L1 blockade immunotherapy in breast cancer

2020 ◽  
Author(s):  
Emi Noguchi ◽  
Tadahiko Shien ◽  
Hiroji Iwata
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
The United States ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Current Status ◽  
Infiltrating Lymphocytes

Abstract Over the past 10 years, immunotherapy with immune checkpoint inhibitors has revolutionized the management of various cancers. However, immunotherapy in breast cancer has not been successful. Breast cancer has long been recognized as an immunologically ‘cold’ tumor, although a higher frequency of tumor-infiltrating lymphocytes present in certain subtypes and an association between tumor-infiltrating lymphocytes and favorable prognosis have been reported. In March 2019, the combination of atezolizumab and nanoparticle albumin-bound paclitaxel was granted accelerated approval in the United States for the treatment of programmed death-ligand 1-positive advanced or metastatic triple-negative breast cancer. This finally opened the door for immune checkpoint blockade therapy for breast cancer. Several clinical trials have been conducted using different combinations of immune checkpoint inhibitors and chemotherapy or targeted agents in various treatment settings for metastatic breast cancer and early-stage breast cancer. In this review, we summarize recent advances in immune checkpoint blockade therapy and predictive biomarkers in breast cancer.

scholarly journals Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies

2021 ◽  
Vol 118 (30) ◽  
pp. e2025570118
Author(s):  
Shamin Li ◽  
Yannick Simoni ◽  
Summer Zhuang ◽  
Austin Gabel ◽  
Shaokang Ma ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Checkpoint ◽  
Tumor Regression ◽  
Tumor Model ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Checkpoint Blockade ◽  
T Cell Response ◽  
Histocompatibility Complex ◽  
Infiltrating Lymphocytes

Neoantigen-specific T cells are strongly implicated as being critical for effective immune checkpoint blockade treatment (ICB) (e.g., anti–PD-1 and anti–CTLA-4) and are being targeted for vaccination-based therapies. However, ICB treatments show uneven responses between patients, and neoantigen vaccination efficiency has yet to be established. Here, we characterize neoantigen-specific CD8+ T cells in a tumor that is resistant to ICB and neoantigen vaccination. Leveraging the use of mass cytometry combined with multiplex major histocompatibility complex (MHC) class I tetramer staining, we screened and identified tumor neoantigen–specific CD8+ T cells in the Lewis Lung carcinoma (LLC) tumor model (mRiok1). We observed an expansion of mRiok1-specific CD8+ tumor-infiltrating lymphocytes (TILs) after ICB targeting PD-1 or CTLA-4 with no sign of tumor regression. The expanded neoantigen-specific CD8+ TILs remained phenotypically and functionally exhausted but displayed cytotoxic characteristics. When combining both ICB treatments, mRiok1-specific CD8+ TILs showed a stem-like phenotype and a higher capacity to produce cytokines, but tumors did not show signs of regression. Furthermore, combining both ICB treatments with neoantigen vaccination did not induce tumor regression either despite neoantigen-specific CD8+ TIL expansion. Overall, this work provides a model for studying neoantigens in an immunotherapy nonresponder model. We showed that a robust neoantigen-specific T-cell response in the LLC tumor model could fail in tumor response to ICB, which will have important implications in designing future immunotherapeutic strategies.

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