Tumor microenvironment has clinical significance in terms of prognosis and therapy prediction

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Clinical Significance ◽  
Effector T Cells ◽  
Treatment Modalities ◽  
Clinical Prognosis ◽  
Current Test ◽  
Colorectal Cancer Cells ◽  
Temporal Interaction ◽  
Therapy Prediction

At this point, the tumor microenvironment (TME) clinical significance in terms of prognosis and therapy prediction has become obvious. The TME is comprised of a varied population of cytokine/chemokine-releasing cells, which results in a local immune response. Colorectal cancer cells also produce antigens that are responsible for initiating an antitumor response. A better clinical prognosis is linked to a large number of effector T cells, which are predominantly made up of CD8+ CTLs, and a low concentration of regulatory T cells. Concentration of PD-L1 and its mutation load are both predictors of a response to anti-PD-L1 treatment. Despite ICI clinical trials showing that ICIs work, patients' responses to ICIs differ depending on the indication. With the emergence of TME-based biomarkers, we will demand additional TME-based biomarkers for more accurate therapies. The spatial-temporal interaction of immune system cells will also need to be investigated, in addition to current test criteria such as the identification of somatic changes, measurement of TMB, loss of HLA locus, and assessment of PD-L1 expression. Also, in order to accurately identify ICI therapy's most favorable recipients, identifying patients who will most benefit from ICI therapy solely or in combination with other treatment modalities is crucial.

The tumor microenvironment: Thousand obstacles for effector T cells

2019 ◽  
Vol 343 ◽  
pp. 103730 ◽  
Author(s):  
Chiara Massa ◽  
Barbara Seliger
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Effector T Cells

517 Regulatory T cell functional identity is sustained by a glucose:lactate axis that is exploited in the tumor microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A553-A553
Author(s):  
McLane Watson ◽  
Paolo Vignali ◽  
Steven Mullet ◽  
Abigail Overacre-Delgoffe ◽  
Ronal Peralta ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Treg Cell ◽  
High Glucose ◽  
Cell Function ◽  
Treg Cells ◽  
Effector T Cells ◽  
Flux Analysis ◽  
Major Barrier ◽  
Suppressive Function

BackgroundRegulatory T (Treg) cells are vital for preventing autoimmunity but are a major barrier to robust cancer immunity as the tumor microenvironment (TME) recruits and promotes their function. The deregulated cellular metabolism of tumor cells leads to a metabolite-depleted, hypoxic, and acidic TME. While the TME impairs the effector function of highly glycolytic tumor infiltrating CD8 T cells, Treg cell suppressive function is maintained. Further, studies of in vitro induced and ex vivo Treg cells reveal a distinct metabolic profile compared to effector T cells. Thus, it may be that the altered metabolic landscape of the TME and the increased activity of intratumoral Treg cells are linked.MethodsFlow cytometry, isotopic flux analysis, Foxp3 driven Cre-lox, glucose tracers, Seahorse extracellular flux analysis, RNA sequencing.ResultsHere we show Treg cells display heterogeneity in terms of their glucose metabolism and can engage an alternative metabolic pathway to maintain their high suppressive function and proliferation within the TME and other tissues. Tissue derived Treg cells (both at the steady state and under inflammatory conditions) show broad heterogeneity in their ability to take up glucose. However, glucose uptake correlates with poorer suppressive function and long-term functional stability, and culture of Treg cells in high glucose conditions decreased suppressive function. Treg cells under low glucose conditions upregulate genes associated with the uptake and metabolism of the glycolytic end-product lactic acid. Treg cells withstand high lactate conditions, and lactate treatment prevents the destabilizing effects of high glucose culture. Treg cells utilize lactate within the TCA cycle and generate phosphoenolpyruvate (PEP), a critical intermediate that can fuel intratumoral Treg cell proliferation in vivo. Using mice with a Treg cell-restricted deletion of lactate transporter Slc16a1 (MCT1) we show MCT1 is dispensable for peripheral Treg cell function but required intratumorally, resulting in slowed tumor growth and prolonged survival.ConclusionsThese data support a model in which Treg cells are metabolically flexible such that they can utilize ‘alternative’ metabolites present in the TME to maintain their suppressive identity. Further, our studies support the notion that tumors avoid immune destruction not only by depriving effector T cells of essential nutrients, but also by metabolically supporting regulatory T cells.

scholarly journals Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments

Blood ◽  
2009 ◽  
Vol 114 (6) ◽  
pp. 1141-1149 ◽  
Author(s):  
Ilona Kryczek ◽  
Mousumi Banerjee ◽  
Pui Cheng ◽  
Linhua Vatan ◽  
Wojciech Szeliga ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
Cancer Patients ◽  
Th17 Cells ◽  
Human Tumor ◽  
Active Role ◽  
Effector T Cells ◽  
Cell Phenotype ◽  
Effector Cells

Abstract Th17 cells play an active role in autoimmune diseases. However, the nature of Th17 cells is poorly understood in cancer patients. We studied Th17 cells, the associated mechanisms, and clinical significance in 201 ovarian cancer patients. Tumor-infiltrating Th17 cells exhibit a polyfunctional effector T-cell phenotype, are positively associated with effector cells, and are negatively associated with tumor-infiltrating regulatory T cells. Tumor-associated macrophages promote Th17 cells through interleukin-1β (IL-1β), whereas tumor-infiltrating regulatory T cells inhibit Th17 cells through an adenosinergic pathway. Furthermore, through synergistic action between IL-17 and interferon-γ, Th17 cells stimulate CXCL9 and CXCL10 production to recruit effector T cells to the tumor microenvironment. The levels of CXCL9 and CXCL10 are associated with tumor-infiltrating effector T cells. The levels of tumor-infiltrating Th17 cells and the levels of ascites IL-17 are reduced in more advanced diseases and positively predict patient outcome. Altogether, Th17 cells may contribute to protective human tumor immunity through inducing Th1-type chemokines and recruiting effector cells to the tumor microenvironment. Inhibition of Th17 cells represents a novel immune evasion mechanism. This study thus provides scientific and clinical rationale for developing novel immune-boosting strategies based on promoting the Th17 cell population in cancer patients.

scholarly journals Tumor Microenvironment: No Effector T Cells without Dendritic Cells

Cancer Cell ◽  
2017 ◽  
Vol 31 (5) ◽  
pp. 614-615 ◽  
Author(s):  
Christina Pfirschke ◽  
Marie Siwicki ◽  
Hsin-Wei Liao ◽  
Mikael J. Pittet
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Microenvironment ◽  
Effector T Cells

scholarly journals Systemic GM-CSF Recruits Effector T Cells into the Tumor Microenvironment in Localized Prostate Cancer

2016 ◽  
Vol 4 (11) ◽  
pp. 948-958 ◽  
Author(s):  
Xiao X. Wei ◽  
Stephen Chan ◽  
Serena Kwek ◽  
Jera Lewis ◽  
Vinh Dao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Effector T Cells ◽  
Localized Prostate Cancer ◽  
Gm Csf

scholarly journals Tumor Cells and the Extracellular Matrix Dictate the Pro-Tumoral Profile of Macrophages in CRC

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5199
Author(s):  
Sara Coletta ◽  
Silvia Lonardi ◽  
Francesca Sensi ◽  
Edoardo D’Angelo ◽  
Matteo Fassan ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Metastatic Potential ◽  
Effector T Cells ◽  
Macrophage Phenotype ◽  
Mhc Ii ◽  
Cytokines And Chemokines ◽  
Antigen Presenting ◽  
Cell Effector

Tumor-associated macrophages (TAMs) are major components of the tumor microenvironment. In colorectal cancer (CRC), a strong infiltration of TAMs is accompanied by a decrease in effector T cells and an increase in the metastatic potential of CRC. We investigated the functional profile of TAMs infiltrating CRC tissue by immunohistochemistry, flow cytometry, ELISA, and qRT-PCR and their involvement in impairing the activation of effector T cells. In CRC biopsies, we evidenced a high percentage of macrophages with low expression of the antigen-presenting complex MHC-II and high expression of CD206. Monocytes co-cultured with tumor cells or a decellularized tumor matrix differentiated toward a pro-tumoral macrophage phenotype characterized by decreased expression of MHC-II and CD86 and increased expression of CD206 and an abundant release of pro-tumoral cytokines and chemokines. We demonstrated that the hampered expression of MHC-II in macrophages is due to the downregulation of the MHC-II transactivator CIITA and that this effect relies on increased expression of miRNAs targeting CIITA. As a result, macrophages become unable to present antigens to CD4 T lymphocytes. Our data suggest that the tumor microenvironment contributes to defining a pro-tumoral profile of macrophages infiltrating CRC tissue with impaired capacity to activate T cell effector functions.

Sorafenib relieves cell-intrinsic and cell-extrinsic inhibitions of effector T cells in tumor microenvironment to augment antitumor immunity

2013 ◽  
Vol 134 (2) ◽  
pp. 319-331 ◽  
Author(s):  
Mei-Ling Chen ◽  
Bo-Shiun Yan ◽  
Wan-Chih Lu ◽  
Mei-Huei Chen ◽  
Sung-Liang Yu ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Antitumor Immunity ◽  
Effector T Cells
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