Abstract 492: Spatial overlap analysis of myeloid and T cell compartments identifies distinct subgroups in the cohort of selected colorectal primary tumors

2019 ◽  
Author(s):  
Natalie Zwing ◽  
Marta Canamero ◽  
Fabien Gaire ◽  
Konstanty Korski
Keyword(s):  
T Cell ◽  
Primary Tumors ◽  
Spatial Overlap ◽  
Cell Compartments ◽  
Overlap Analysis

Expression of CYP3A4 as a predictor of response to chemotherapy in peripheral T-cell lymphomas

Blood ◽  
2007 ◽  
Vol 110 (9) ◽  
pp. 3345-3351 ◽  
Author(s):  
Cristina Rodríguez-Antona ◽  
Susanna Leskelä ◽  
Magdalena Zajac ◽  
Marta Cuadros ◽  
Javier Alvés ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Response ◽  
Cell Lines ◽  
Current Therapy ◽  
Fish Analysis ◽  
Primary Tumors ◽  
Chemotherapy Drugs ◽  
T Cell Lymphomas ◽  
Response To Chemotherapy ◽  
Peripheral T Cell Lymphomas

Abstract Peripheral T-cell lymphomas (PTCLs) are aggressive tumors in which the current therapy based on multiagent chemotherapy is not successful. Since cytochrome P450 3A subfamily (CYP3A) enzymes are involved in the inactivation of chemotherapy drugs, we hypothesized that CYP3A and P-glycoprotein (MDR1) expression in these lymphomas could result in a poor clinical response. We measured tumoral CYP3A and MDR1 mRNA content in 44 T-cell lymphomas, finding a large variation in CYP3A expression. Multiplex polymerase chain reaction (PCR) analysis and fluorescence in situ hybridization (FISH) analysis showed genomic gains affecting CYP3A and MDR1 genes in T-cell lines and primary tumors, suggesting that this could be the mechanism underlying the tumoral expression variation. To test whether the tumoral expression of CYP3A and/or MDR1 could influence PTCL treatment outcome, their expression levels were compared with the clinical response and survival of the patients, finding that a high tumoral expression of CYP3A4 was significantly associated with a lower complete remission rate. This was further investigated with cell lines stably expressing CYP3A4 that exhibited an increased resistance to doxorubicin and etoposide. In conclusion, a high CYP3A4 tumoral expression could be useful to predict poor response to the standard PTCL chemotherapy; in these cases alternative chemotherapy combinations or doses should be explored.

scholarly journals Comparative Multiomic Analysis Reveals Low T Cell Infiltration as the Primary Feature of Tobacco Use in HPV(+) Oropharyngeal Cancer

2021 ◽  
Author(s):  
Benjamin M Wahle ◽  
Paul Zolkind ◽  
Ricardo Ramirez ◽  
Zachary L Skidmore ◽  
Angela Mazul ◽  
...  
Keyword(s):  
T Cell ◽  
Tobacco Use ◽  
Disease Free Survival ◽  
Oncologic Outcomes ◽  
Cell Infiltration ◽  
Tobacco Exposure ◽  
Primary Tumors ◽  
T Cell Infiltration ◽  
Mutational Burden ◽  
Whole Exome

Purpose: Tobacco use is an independent adverse prognostic feature in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Despite this, the biologic features associated with tobacco use have not been systematically investigated in this population. We sought to characterize the genomic and immunologic features of HPV(+) OPSCC associated with tobacco use and adverse oncologic outcomes. Experimental Design: Whole exome sequencing of 47 primary HPV(+) OPSCC tumors was performed to investigate mutational differences associated with tobacco exposure. To characterize the tumor immune microenvironment (TIME), targeted mRNA hybridization was performed and immunohistochemical (IHC) staining was used to validate these findings. Results: Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at the time of diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T>C substitutions and a lower proportion of mutational signatures typically observed in HPV(+) OPSCC tumors, but was not associated with increases in mutational burden or the rate of recurrent oncogenic mutations. Conclusions: In HPV(+) OPSCC, low T cell infiltration of primary tumors is associated with current tobacco use and worse oncologic outcomes. Rather than an increased mutational burden, tobacco's primary and clinically relevant association is immunosuppression of the primary TIME. An objective clinical assay like the TGEP, which quantifies immune infiltration of the primary TIME, may have value for HPV(+) OPSCC risk stratification in future clinical trials.

scholarly journals Plasma Membrane Calcium ATPase Regulates Stoichiometry of CD4+ T-Cell Compartments

2021 ◽  
Vol 12 ◽  
Author(s):  
Maylin Merino-Wong ◽  
Barbara A. Niemeyer ◽  
Dalia Alansary
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Immune Responses ◽  
Chromatin Immunoprecipitation ◽  
Expression Patterns ◽  
Calcium Atpase ◽  
Cd4 T Cell ◽  
Plasma Membrane Calcium Atpase ◽  
Cell Compartments

Immune responses involve mobilization of T cells within naïve and memory compartments. Tightly regulated Ca2+ levels are essential for balanced immune outcomes. How Ca2+ contributes to regulating compartment stoichiometry is unknown. Here, we show that plasma membrane Ca2+ ATPase 4 (PMCA4) is differentially expressed in human CD4+ T compartments yielding distinct store operated Ca2+ entry (SOCE) profiles. Modulation of PMCA4 yielded a more prominent increase of SOCE in memory than in naïve CD4+ T cell. Interestingly, downregulation of PMCA4 reduced the effector compartment fraction and led to accumulation of cells in the naïve compartment. In silico analysis and chromatin immunoprecipitation point towards Ying Yang 1 (YY1) as a transcription factor regulating PMCA4 expression. Analyses of PMCA and YY1 expression patterns following activation and of PMCA promoter activity following downregulation of YY1 highlight repressive role of YY1 on PMCA expression. Our findings show that PMCA4 adapts Ca2+ levels to cellular requirements during effector and quiescent phases and thereby represent a potential target to intervene with the outcome of the immune response.

scholarly journals Naïve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Pavel V. Shelyakin ◽  
Ksenia R. Lupyr ◽  
Evgeny S. Egorov ◽  
Ilya A. Kofiadi ◽  
Dmitriy B. Staroverov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Subset ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cell Compartments ◽  
Expression Of Genes ◽  
Tcr Repertoire ◽  
Antigen Presenting

The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4+ and CD8+ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4+ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve Treg (CD4+CD45RA+CD27+CD25+) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve Treg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve Treg selection. Furthermore, the naïve Treg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.

DJ-1 depletion prevents immunoaging in T-cell compartments

immuneACCESS ◽  
2022 ◽  
Author(s):  
N Zeng ◽  
C Capelle ◽  
A Baron ◽  
T Kobayashi ◽  
S Cire ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Compartments

Overcoming resistance to anti-PD-1 with tumor agnostic NBTXR3: From bench to bed side.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2591-2591
Author(s):  
Tanguy Y. Seiwert ◽  
Colette Shen ◽  
Jessica M. Frakes ◽  
Jiaxin Niu ◽  
Jared Weiss ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cell ◽  
Tumor Regression ◽  
Single Agent ◽  
Locally Advanced ◽  
Cd8 T Cell ◽  
Intratumoral Injection ◽  
Post Treatment ◽  
Primary Tumors ◽  
Systemic Control

2591 Background: Despite recent advances, resistance to immune checkpoint inhibitors (ICI), observed in over 80% of treated patients, is currently the main challenge in immuno-oncology. Intense efforts are being made to identify combination therapies that could improve ICI response rates. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase radiation therapy (XRT) dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Here we present evidence that NBTXR3 activated by XRT primes the immune system, producing an anti-tumor response, including activation of the cGAS-STING pathway, that overcomes anti-PD-1 resistance both in mice models and patients. Methods: Abscopal assays were conducted in immunocompetent mice. Anti-PD-1 sensitive or resistant tumor cell lines, were injected in both flanks of mice. Intratumoral injection of NBTXR3 (or vehicle) followed by XRT was performed in right flank (primary) tumors only. Some mice also received anti-PD-1 injections. Tumor growth was monitored, and tumor immune cell infiltrates analyzed by immunohistochemistry (IHC). Separately, in the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced soft tissue sarcoma (STS) received either NBTXR3+XRT or XRT alone followed by tumor resection. Pre- and post-treatment tumor samples from patients in both groups were analyzed by IHC and Digital Pathology for immune biomarkers. The safety and efficacy (RECIST 1.1/iRECIST) of NBTXR3 plus stereotactic body radiotherapy (SBRT) in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers [NCT03589339]. Results: Pre-clinical studies demonstrated that NBTXR3+XRT induces an immune response not observed with XRT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3+XRT treated and untreated tumors compared to XRT alone. Similarly, increased CD8+ T-cell and decreased FOXP3+ Treg density (pre- vs post-treatment) was observed in tumor tissues from STS patients treated with NBTXR3+XRT. Furthermore, NBTXR3+XRT in combination with anti-PD-1 improved local and systemic control in mice bearing anti-PD-1 resistant lung tumors, as well as reduced the number of spontaneous lung metastases. Preliminary efficacy data from the first in human trial of NBTXR3+XRT in combination with anti-PD-1 showed tumor regression in the majority of patients (8/9). Of note, tumor regression was observed in 6/7 pts who had progressed on prior anti-PD-1. Conclusions: The clinical efficacy of NBTXR3+XRT has been demonstrated as a single agent. We now demonstrate that it potentiates anti-PD-1 treatment to overcome resistance mechanisms. These results highlight the potential of NBTXR3+XRT to positively impact the immuno-oncology field. Clinical trial information: NCT03589339.

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