CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment

Cell ◽  
2021 ◽  
Author(s):  
Mauro Di Pilato ◽  
Raphael Kfuri-Rubens ◽  
Jasper N. Pruessmann ◽  
Aleksandra J. Ozga ◽  
Marius Messemaker ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cytotoxic T Cells ◽  
To Receive ◽  
Critical Survival ◽  
Survival Signals

scholarly journals Tumor microenvironment in triple-negative breast cancer: the correlation of tumor-associated macrophages and tumor-infiltrating lymphocytes

2021 ◽  
Author(s):  
H. Kuroda ◽  
T. Jamiyan ◽  
R. Yamaguchi ◽  
A. Kakumoto ◽  
A. Abe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Free Survival ◽  
Infiltrating Lymphocytes

Abstract Purpose Immune cells such as cytotoxic T cells, helper T cells, B cells or tumor-associated macrophages (TAMs) contribute to the anti-tumor response or pro-tumorigenic effect in triple negative breast cancer (TNBC). The interrelation of TAMs, T and B tumor-infiltrating lymphocytes (TILs) in TNBC has not been fully elucidated. Methods We evaluated the association of tumor-associated macrophages, T and B TILs in TNBC. Results TNBCs with a high CD68+, CD163+ TAMs and low CD4+, CD8+, CD20+ TILs had a significantly shorter relapse-free survival (RFS) and overall survival (OS) than those with low CD68+, CD163+ TAMs and high CD4+, CD8+, CD20+ TILs. TNBCs with high CD68+ TAMs/low CD8+ TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD68+ TAMs/high CD8+ TILs, low CD68+ TAMs/high CD8+ TILs, and low CD68+/low CD8+. TNBCs with high CD163+ TAMs/low CD8+, low CD20 + TILs showed a significantly shorter RFS and OS and a significantly poorer prognosis than those with high CD163+ TAMs/high CD8+ TILs and high CD163+ TAMs /high CD20+ TILs. Conclusions Our study suggests that TAMs further create an optimal tumor microenvironment (TME) for growth and invasion of cancer cells when evasion of immunoreactions due to T and B TILs occurs. In TNBCs, all these events combine to affect prognosis. The process of TME is highly complex in TNBCs and for an improved understanding, larger validation studies are necessary to confirm these findings.

Thyroid status regulates tumor microenvironment delineating breast cancer fate

2021 ◽  
Author(s):  
Helena Andrea Sterle ◽  
Ximena Hildebrandt ◽  
Matías Valenzuela Álvarez ◽  
María Alejandra Paulazo ◽  
Luciana Mariel Gutierrez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Lung Metastasis ◽  
Cytotoxic T Cells ◽  
Suppressor Cells ◽  
Thyroid Status ◽  
Cd8 Cells ◽  
Regulatory T Lymphocytes ◽  
Starting Point

The patient’s hormonal context plays a crucial role in the outcome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth and dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, a delayed tumor growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also exhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens, but increased activated CD8+ cells and IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. The better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast cancer.

scholarly journals Preclinical and clinical development of therapeutic antibodies targeting functions of CD47 in the tumor microenvironment

2020 ◽  
Vol 3 (3) ◽  
pp. 179-192
Author(s):  
Sukhbir Kaur ◽  
Kyle V Cicalese ◽  
Rajdeep Banerjee ◽  
David D Roberts
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Cytotoxic T Cells ◽  
Regulatory Protein ◽  
Immune Surveillance ◽  
Hematologic Malignancies ◽  
Clinical Development ◽  
Surface Glycoprotein ◽  
Cell Surface Glycoprotein ◽  
Thrombospondin 1

ABSTRACT CD47 is a ubiquitously expressed cell surface glycoprotein that functions as a signaling receptor for thrombospondin-1 and as the counter-receptor for signal regulatory protein-α (SIRPα). Engaging SIRPα on macrophages inhibits phagocytosis, and CD47 thereby serves as a physiological marker of self. However, elevated CD47 expression on some cancer cells also protects tumors from innate immune surveillance and limits adaptive antitumor immunity via inhibitory SIRPα signaling in antigen-presenting cells. CD47 also mediates inhibitory thrombospondin-1 signaling in vascular cells, T cells, and NK cells, and blocking inhibitory CD47 signaling on cytotoxic T cells directly increases tumor cell killing. Therefore, CD47 functions as an innate and adaptive immune checkpoint. These findings have led to the development of antibodies and other therapeutic approaches to block CD47 functions in the tumor microenvironment. Preclinical studies in mice demonstrated that blocking CD47 can limit the growth of hematologic malignancies and solid tumors and enhance the efficacy of conventional chemotherapy, radiation therapy, and some targeted cancer therapies. Humanized CD47 antibodies are showing promise in early clinical trials, but side effects related to enhanced phagocytic clearance of circulating blood cells remain a concern. Approaches to circumvent these include antibody preloading strategies and development of antibodies that recognize tumor-specific epitopes of CD47, SIRPα antibodies, and bivalent antibodies that restrict CD47 blockade to specific tumor cells. Preclinical and clinical development of antibodies and related biologics that inhibit CD47/SIRPα signaling are reviewed, including strategies to combine these agents with various conventional and targeted therapeutics to improve patient outcome for various cancers.

Pembrolizumab treatment increases chemotaxis of cytotoxic T cells in head and neck cancer patients within the adenosine‐rich tumor microenvironment

2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Hannah S. Newton ◽  
Ameet A. Chimote ◽  
Vaibhavkumar S. Gawali ◽  
Sarah Palackdharry ◽  
David Hildeman ◽  
...  
Keyword(s):  
T Cells ◽  
Head And Neck Cancer ◽  
Tumor Microenvironment ◽  
Head And Neck ◽  
Cancer Patients ◽  
Neck Cancer ◽  
Cytotoxic T Cells

scholarly journals STUDY OF TUMOR MICROENVIRONMENT AND HOST RESPONSE IN COLORECTAL CANCER: IMMUNOHISTOCHEMICAL AND CLINICOPATHOLOGICAL APPROACH

2019 ◽  
pp. 32-37
Author(s):  
NORIA OTHMAN RAFFALLA ◽  
SUZAN MOHAMED FAROUK HELAL ◽  
AMANY ABD EL-BARY ABD EL-LATIF ◽  
RASHA OMAR ELSAKA
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Regulatory T Cells ◽  
Cytotoxic T Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Associated Macrophages ◽  
Tissue Samples ◽  
Level Of Significance

Objective: This study aimed to evaluate the immunohistochemical expression of forkhead boxP3 (Foxp3), CD8, CD68, and CD21 in stroma between tumor cells of colorectal cancer (CRC) patients and examines the relationship between these variables and clinicopathological parameter and patients’ prognosis. Methods: In this work, 50 cases of colorectal carcinomas were included and immunohistochemical evaluation of Foxp3, CD8, CD68, and CD21 in tumor tissue samples. Results: Tumor-infiltrating lymphocytes (TILs) including cytotoxic T cells and regulatory T cells as well as tumor-associated macrophages and follicular dendritic cells (FDCs) were studied in the stroma of the tumor using immunostaining technique for CD8, Foxp3, CD68, and CD21, respectively. Cases were followed up. CD8-positive cytotoxic T cells, Foxp3-positive regulatory T cells, and CD21 positive-FDCs were significantly more pronounced in early tumors and those with longer overall survival. On the other hand, CD68 positive macrophages were more encountered in late stage and metastatic tumors as well as tumors with shorter overall survival, but these results not reached the level of significance. Conclusion: We concluded that (TILs) and FDCs are conferring better prognosis in CRCs, they may act synergistically in stimulating a protective immune response in the tumor microenvironment that hinders tumor progression, while the role of tumor-associated macrophages in CRCs is still controversial and needs further studies.

scholarly journals 255 Investigating VISTA’s role intrinsic to T cells in the tumor microenvironment

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A276-A276
Author(s):  
Cassandra Gilmour ◽  
Li Wang ◽  
Juan Dong ◽  
Sarah Stone ◽  
Keman Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Tumor Immunity ◽  
Patient Survival ◽  
Cytotoxic T Cells ◽  
Peripheral Tolerance ◽  
Checkpoint Blockade

BackgroundCancer immunotherapies, specifically checkpoint blockade therapies, have demonstrated clinical importance for long term patient survival. One of the major limitations to checkpoint blockade therapies, is the low response rate: ~30% with anti-CTLA4 and anti-PD1 treatment. This may be due to heterogeneity of the patients‘ immune system and the tumor microenvironment including T cell inhibitions. There is a clear need to study this phenomenon and develop additional therapies for long term survival to include a broad range of patients. V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA) is a suppressive protein expressed on many cell types in the tumor microenvironment including cytotoxic T cells. VISTA’s role on T cells has been described as maintaining quiescence and peripheral tolerance in a graft vs host disease model, but is not fully understood in context of the tumor microenvironment.MethodsWe use a series of invivo experiments, including T cell specific VISTA knock outs, to understand the role of VISTA on T cells in the tumor microenvironment.ResultsHere we show a series of in vivo experiments that suggest VISTA has a potent intrinsic role on T cells and therefore anti-tumor immunity. Using a T cell specific VISTA knock out, our results suggest that the absence of VISTA on T cells in combination with anti-CTLA4 and vaccine is a very powerful tumor suppressor compared to vaccine and anti-CTLA4 treatment alone. These results also indicate that the absence of VISTA alters the phenotype of cytotoxic T cells in several ways including the production of inflammatory cytokines.ConclusionsOur preliminary data provides foundation to study VISTA’s role intrinsic to T cells in the tumor microenvironment and how disrupting VISTA’s influence intrinsic to T cells may be advantageous for anti-tumor immunity and long term patient survival.Ethics ApprovalAll in vivo studies were reviewed and approved by Institutional Animal Care and Use Committee (Approval number 2019–2142).

iRGD in combination with IL-2 reprograms tumor immunosuppression.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 55-55
Author(s):  
Gregory P. Botta ◽  
Tatiana Hurtado De Mendoza ◽  
Harri Jarvelainen ◽  
Erkki Ruoslahti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Mouse Models ◽  
Cd8 T Cells ◽  
Cytotoxic T Cells ◽  
Single Agent ◽  
Ductal Adenocarcinoma ◽  
Live Cells ◽  
Subsequent Increase

55 Background: Fibrotic solid tumors have lagged in immunotherapy efficacy. Although breast cancer (BC) shows modest single-agent activity, pancreatic ductal adenocarcinoma (PDAC) immunotherapy has repeatedly failed in clinical trials. A protective desmoplastic, inflammatory reaction encapsulates BC and PDAC where it can make up to 80% of the tumor microenvironment (TME). Reports in BC and PDAC patients and mouse models suggest that tumoricidal effector CD8+ T-cells are indeed present, yet suppressed by regulatory CD4+/CD25+/FoxP3+ T-cells (Tregs) and myeloid cells. Long-term PDAC and BC survivors harbor CD8+ T-cells by immunohistochemistry (IHC), and although inactivated (CD107a-), they are not terminally exhausted (PD-1low). Further, when CD8+ T-cells were found in large quantities within a treatment-naïve biopsy, that patient had an increased overall survival. We hypothesize that low doses of the T-cell proliferative cytokine IL-2 can class switch the TME T-cells if specifically concentrated within the tumor by the stroma-penetrating peptide iRGD. Methods: Subcutaneous BC tumors (4T1) and PDAC (KPC ) tumors were formed in immunocompetent mouse models. Mice were treated with either vehicle, iRGD, IL-2, or both in combination. Tumors were preserved for IHC or enzymatically digested for FACS. CD45+ live cells were fluorescently labeled for effector T-cells (CD4+/CD44+ or CD8+/CD44+), Tregs (CD4+/CD25+/FoxP3+), or cytotoxic T-cells (CD8+/CD44+/Granzyme B+/IL-2+). Results: Versus normal controls, tumors from BC and PDAC both showed a subsequent increase in bulk CD3+ T-cells within the tumor microenvironment (14.3% ± 5 vs. 27.6% ± 8). A significant increase in CD3+ T-cells within all tumors (10%) occured with iRGD only, IL-2 only, or iRGD + IL-2 treatment. Whereas sub-populations of T-cells in the iRGD only and IL-2 only treatment groups was overwhelming composed of Tregs (5%) at CD4/Treg and CD8/Treg ratios of 1.75 and 0.5 respectively, the combination of iRGD + IL-2 shifted the T-cell sub-populations away from Tregs (1.5%) and towards increased CD4/Treg and CD8/Treg ratios (4 and 12 respectively). Conclusions: The combination of iRGD + IL-2 is capable of reprogramming the immunosuppressive Treg tumor microenvironment, increasing effector CD4+ and CD8+ T-cells.

Sparsity of dendritic cells and cytotoxic T cells in tumor microenvironment may lead to recurrence in basal cell carcinoma

2020 ◽  
Vol 59 (10) ◽  
pp. 1258-1263
Author(s):  
Burcu Beksaç ◽  
Nilsel İlter ◽  
Özlem Erdem ◽  
Pinar Çakmak ◽  
Seyhan Çenetoğlu ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Tumor Microenvironment ◽  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Cytotoxic T Cells
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