scholarly journals P2.04-26 Single Cell Proteomics Profiling of Live T-Cells in KRAS+ and MET-Amp NSCLC to Predict Immune Checkpoint Inhibitor Response

2019 ◽  
Vol 14 (10) ◽  
pp. S718
Author(s):  
Z. Lim ◽  
X. Wu ◽  
M. Hafez ◽  
H. Albandar ◽  
L. Zhu ◽  
...  
Keyword(s):  
T Cells ◽  
Single Cell ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor

scholarly journals 805 Clonal, activated CD8+ T cells recognizing cardiac alpha-myosin drive immune checkpoint inhibitor associated myocarditis in mice

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A842-A842
Author(s):  
Margaret Axelrod ◽  
Wouter Meijers ◽  
Elie Tannous ◽  
Xiaopeng Sun ◽  
Juan Qin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Animal Experiments ◽  
Eligibility Criteria

BackgroundNearly half of all U.S. oncology patients meet FDA eligibility criteria to receive treatment with an immune checkpoint inhibitor (ICI). With increasing use of ICIs, preventing, diagnosing and treating immune-related adverse events (irAEs) are urgent clinical challenges. Myocarditis is an uncommon irAE, affecting < 1% of ICI-treated patients, but is highly fatal, with a mortality rate of nearly 50%. Genetically altered Pdcd1-/-Ctla4± mice die prematurely and specifically due to myocarditis. This model recapitulates the clinical and pathological features of ICI-myocarditis, including abundant cardiac infiltrating CD8+ T cells. The potential autoantigen(s) involved in ICI-myocarditis are unknown for both human disease and our murine model.MethodsWe used Pdcd1-/-Ctla4± mice on the C57BL6 background as a model of ICI-myocarditis. Single cell RNA and T cell receptor (TCR) sequencing was performed on sorted CD45+ cardiac immune cells from four affected Pdcd1-/-Ctla4± mice compared to six healthy wild type mice. The most three clonal TCRs (TCR-A, B, C), derived from two independent Pdcd1-/-Ctla4± mice, were reconstructed using stiTChR and transduced into reporter T cell lines for antigen discovery. Alpha-myosin was selected as a candidate autoantigen due to lack of presentation in the thymus. Reporter TCR-A, B, and C cells were screened using a library of overlapping 20 amino acid peptides derived from alpha-myosin in co-culture with bone marrow derived dendritic cells.ResultsTreatment with anti-CD8, but not anti-CD4, depleting antibodies rescues survival of Pdcd1-/-Ctla4± mice. Furthermore, adoptive transfer of splenocytes from Pdcd1-/-Ctla4± mice with myocarditis to Rag1-/- recipient mice was sufficient to induce fatal myocarditis. Single cell RNA/TCR sequencing on the cardiac immune infiltrate of Pdcd1-/-Ctla4± mice identified highly activated, clonal CD8+ T cells as the dominant cell population. The TCR-A cell line, the most clonal TCR identified in single cell TCR sequencing, activates NFAT, NFkB, and AP-1 reporters in response to the alpha-myosin epitope VIQYFASI. The TCR-B and TCR-C cell lines activate their reporters in response to the alpha myosin peptide DALLVIQWNIRAFMGVKNWP, indicating that alpha-myosin is an autoantigen in this mouse model of ICI-myocarditis.ConclusionsClonal, activated CD8+ T cells are critical for the development of ICI-myocarditis. Alpha-myosin is an autoantigen recognized by the most clonal cardiac CD8+ T cells. Efforts are currently underway to determine whether human TCRs derived from ICI-myocarditis samples recognize similar antigens. These studies are the first to identify a candidate autoantigen in ICI-myocarditis and may yield new insights into irAE pathogenesis.Ethics ApprovalAll animal experiments were in accordance with the VUMC Institutional Animal Care and Use Committee (IACUC), protocol # M2000067

scholarly journals Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002181
Author(s):  
Erin F Simonds ◽  
Edbert D Lu ◽  
Oscar Badillo ◽  
Shokoufeh Karimi ◽  
Eric V Liu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Immune Evasion ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Prolonged Survival ◽  
Tumor Associated Macrophages ◽  
The Brain ◽  
Immune Profiling

BackgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.ResultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.

Abstract LB037:89ZED88082A PET imaging to visualize CD8+T cells in patients with cancer treated with immune checkpoint inhibitor

2021 ◽  
Author(s):  
Laura Kist de Ruijter ◽  
Pim P. van de Donk ◽  
Jahlisa S. Hooiveld-Noeken ◽  
Danique Giesen ◽  
Alexander Ungewickell ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Pet Imaging ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Patients With Cancer

PS-025-Elevated tissue homing of monocytes and increased cytotoxic activity of CD8+ T-cells in immune checkpoint inhibitor-induced hepatitis

2019 ◽  
Vol 70 (1) ◽  
pp. e19-e20
Author(s):  
Cathrin L.C. Gudd ◽  
Tong Liu ◽  
Evangelos Triantafyllou ◽  
David J. Pinato ◽  
You Yone ◽  
...  
Keyword(s):  
T Cells ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor

scholarly journals Influence of Tumor Immune Infiltration on Immune Checkpoint Inhibitor Therapeutic Efficacy: A Computational Retrospective Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Rong Liu ◽  
Fang Yang ◽  
Ji-Ye Yin ◽  
Ying-Zi Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Therapeutic Efficacy ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Progression Free Survival ◽  
Cytolytic Activity ◽  
Consensus Clustering ◽  
Tfh Cells

The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.

scholarly journals Identification of STAT5A as drug screening biomarker and immune checkpoint inhibitor in stomach adenocarcinoma via comprehensive bioinformatics analysis

2020 ◽  
Author(s):  
tao lin ◽  
Shuang Wu ◽  
Jianwen Wen ◽  
Wentao Zhang
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Drug Screening ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Disease Free Survival ◽  
Genetic Alterations ◽  
Apoptosis Pathway ◽  
Immune Biomarkers

Abstract Background: Gastric cancer is one of the fatal diseases and the third leading cause of cancer-related deaths worldwide. Limited drugs or therapeutic methods could be applied for these patients, and their prognosis was poor median overall survival (OS) of about 10 months. Increasing evidences demonstrated STAT gene family as biomarkers for prognosis, immunotherapy and drug screening.Methods: The drug screening biomarker and immune checkpoint inhibitor among STAT family were explored with several online bioinformatics tools.Results: The level STAT1/3/5A were significantly increased in STAD tissues compared with normal tissues. Methylation could downregulate STAT family expression, except STAT4. STAT1/5A/5B/6 may functioned as biomarkers for the prognosis of STAD patients. amplification and mRNA high were the most common genetic alteration form, genetic alterations could affect the disease-free survival but not overall survival of STAD patients. STAT family were involved in the activation of apoptosis pathway, EMT pathway, and hormone ER pathways, and the inhibition of cell cycle pathway, and DNA damage response pathways. Moreover, STAT5A and STAT5B were related with the drug sensitivity. Immune infiltration revealed that STAT5A level showed significant correlation with the abundance of immune cells (CD8+ T cells, CD4+ T cells, Macrophage, Neutrphils and Dendritic cells) and the level immune biomarkers. Somatic copy number alterations of STAT5A could significantly inhibit immune cell infiltration.Conclusions: STAT5A act as drug screening biomarker and immune checkpoint inhibitor in STAD.

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