T cell exclusion, immune privilege, and the tumor microenvironment

Science ◽  
2015 ◽  
Vol 348 (6230) ◽  
pp. 74-80 ◽  
Author(s):  
Johanna A. Joyce ◽  
Douglas T. Fearon
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Stromal Cells ◽  
Cytotoxic T Cells ◽  
Immune Privilege ◽  
Immune Attack ◽  
T Cell Exclusion

Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. This requires not only that cancer-specific T cells be generated, but also that these T cells physically contact cancer cells. The coexistence in some patients of cancer cells and T cells that recognize them indicates that tumors may exhibit the phenomenon of immune privilege, in which immunogenic tissue is protected from immune attack. Here, we review the evidence that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells. Overcoming this T cell checkpoint may thus enable optimal immunotherapy.

scholarly journals Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 65
Author(s):  
Vladimir Voynov ◽  
Paul J. Adam ◽  
Andrew E. Nixon ◽  
Justin M. Scheer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Clinical Data ◽  
Solid Tumor ◽  
Clinical Studies ◽  
Mode Of Action ◽  
Cytotoxic T Cells ◽  
Molecular Structures ◽  
Bispecific Antibodies

T-cell Engaging bispecific antibodies (TcEs) that can re-direct cytotoxic T-cells to kill cancer cells have been validated in clinical studies. To date, the clinical success with these agents has mainly been seen in hematologic tumor indications. However, an increasing number of TcEs are currently being developed to exploit the potent mode-of-action to treat solid tumor indications, which is more challenging in terms of tumor-cell accessibility and the complexity of the tumor microenvironment (TME). Of particular interest is the potential of TcEs as an immunotherapeutic approach for the treatment of non-immunogenic (often referred to as cold) tumors that do not respond to checkpoint inhibitors such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies. This has led to considerable discovery efforts for, firstly, the identification of tumor selective targeting approaches that can safely re-direct cytotoxic T-cells to cancer cells, and, secondly, bispecific antibodies and their derivatives with drug-like properties that promote a potent cytolytic synapse between T-cells and tumor cells, and in the most advanced TcEs, have IgG-like pharmacokinetics for dosing convenience. Based on encouraging pre-clinical data, a growing number of TcEs against a broad range of targets, and using an array of different molecular structures have entered clinical studies for solid tumor indications, and the first clinical data is beginning to emerge. This review outlines the different approaches that have been taken to date in addressing the challenges of exploiting the TcE mode-of-action for a broad range of solid indications, as well as opportunities for future discovery potential.

Stromal Cells Protect B-CLL Cells from Killing by Antigen-Specific Cytotoxic T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2814-2814
Author(s):  
Katja Zirlik ◽  
Meike Burger ◽  
Philipp Brantner ◽  
Gabriele Prinz ◽  
Maike Buchner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cytotoxic T Cells ◽  
Protective Effects ◽  
Stromal Cell Line

Abstract B-cell malignancy-derived immunoglobulin (idiotype) and survivin, a member of the inhibitor of apoptosis gene family and a shared tumor-associated antigen, are expressed by B-CLL cells. Idiotype- and survivin-specific cytotoxic T cells (CTLs), capable of lysing primary autologous B-CLL cells, can be induced in patients with B-CLL. However, the leukemia cell microenvironment was shown to protect B-CLL cells from apoptosis. The protective effects of stromal cells can be reversed by CXCR4 antagonists in vitro and resensitize CLL cells to spontaneous and chemotherapy-induced apoptosis. The aim of the present study is to investigate whether stromal cell contact impairs CLL killing by CTLs raised against immunoglobulin- or survivin-derived peptides and whether the addition of CXCR4 inhibitors enhances T cell mediated cytotoxicity. To analyze the T cell response, we isolated CD8+ T cells and PBMCs from HLA-A2+ healthy donors. PBMCs were differentiated into dendritic cells (DCs) and CD40-activated B cells. CD8+ T cells were primarily stimulated with peptide-pulsed DCs and then restimulated weekly with peptide-pulsed CD40-activated B cells. Heteroclitic framework region (FR−), heteroclitic complementarity-determining region (CD−) derived peptides, and native and heteroclitic survivin-derived peptides were used for CTL induction. As expected, heteroclitic peptide modifications increased the binding affinity to HLA-A*0201 compared to the native peptide as predicted by the Parker Score (Median change of predicted half-time of dissociation to HLA class I molecules 1429 minutes) and measured by the T2 binding assay (Fluorescence Index (FI) native 0.2; FI heteroclitic 0.9). Cytotoxicity of T cells was assessed by chromium release assay and by flow cytometry against CFSE-labelled CLL cells alone and in co-culture with unlabelled stromal cells in the absence or presence of CXCR4 blocking agents. The induced CTLs efficiently lysed allogenic HLA-A2+ CLL cells (mean cytotoxicity at 30:1, 10:1, 3:1 effector-to-target (E:T) ratio: 15,5%+/−2,8; 7,5%+/−2,8; and 1,9%+/− 0,6), but not HLA-A2 negative CLL cells. Co-culture of CLL cells with the murine stromal cell line M2-10B4 resulted in protection of CLL cells from lysis by antigen-specific cytotoxic T cells in vitro, indeed suggesting a protective role of the microenvironment (mean cytotoxicity at 30:1, 10:1, 3:1 E:T ratio: 5,2%+/−4,1; 0,4%+/−1,6; 1,2%+/−2,0). In contrast to apoptosis induced by fludarabine, CXCR4 blocking agents did not reverse the protective effects of the stromal cell line on T cell mediated cytotoxicity (mean cytotoxicity 30:1, 10:1, 3:1 E:T ratio: 3,1%+/−2,4; 0,8%+/−2,5; 2,3%+/−1,6). These data indicate that the microenvironment may exert protective effects against immunotherapeutic strategies in CLL. However, the protective interaction is not entirely mediated by the CXCR4 - CXCL12 axis. Additional cell-cell interactions appear to play a role and need to be identified as therapeutic targets in order to effectively interrupt the protective effect of the microenvironment on T cell mediated cytotoxicity of B-CLL cells.

scholarly journals The Fas counterattack: Fas-mediated T cell killing by colon cancer cells expressing Fas ligand.

1996 ◽  
Vol 184 (3) ◽  
pp. 1075-1082 ◽  
Author(s):  
J O'Connell ◽  
G C O'Sullivan ◽  
J K Collins ◽  
F Shanahan
Keyword(s):  
Colon Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Surface ◽  
Cancer Cells ◽  
Antisense Oligonucleotide ◽  
Fas Ligand ◽  
Immune Privilege ◽  
Colon Cancer Cells ◽  
Rt Pcr

Tumors escape immunological rejection by a diversity of mechanisms. In this report, we demonstrate that the colon cancer cell SW620 expresses functional Fas ligand (FasL), the triggering agent of Fas receptor (FasR)-mediated apoptosis within the immune system. FasL mRNA and cell surface FasL were detected in SW620 cells using reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. We show that SW620 kills Jurkat T cells in a Fas-mediated manner. FasR-specific antisense oligonucleotide treatment, which transiently inhibited FasR expression, completely protected Jurkat cells from killing by SW620. FasL-specific antisense oligonucleotide treatment of SW620 inhibited its Jurkat-killing activity. FasL has recently been established as a mediator of immune privilege in mouse retina and testis. Our finding that colon cancer cells express functional FasL suggests it may play an analogous role in bestowing immune privilege on human tumors. HT29 and SW620 colon cancer cells were found to express FasR mRNA and cell surface FasR using RT-PCR and immunofluorescence flow cytometry, respectively. However, neither of these cells underwent apoptosis after treatment by the anti-FasR agonistic monoclonal antibody CH11. Our results therefore suggest a Fas counterattack model for immune escape in colon cancer, whereby the cancer cells resist Fas-mediated T cell cytotoxicity but express functional FasL, an apoptotic death signal to which activated T cells are inherently sensitive.

scholarly journals Immune suppressed tumor microenvironment by exosomes derived from gastric cancer cells via modulating immune functions

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Liu ◽  
Shaoxian Wu ◽  
Xiao Zheng ◽  
Panpan Zheng ◽  
Yuanyuan Fu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cell Lines ◽  
Gastric Cancer Cell ◽  
Gastric Cancer Cells ◽  
Gastric Cancer Cell Lines

Abstract Gastric cancer is one of the leading causes of cancer-related death due to late diagnosis with high metastatic frequency. In this study, the impact of tumor secreted exosomes on immune function in the tumor environment was investigated using exosomes isolated from gastric cancer cell lines MKN-28, MKN-45, and SGC-7901. Results show that exosomes derived from all of these cell lines changed the gene expression and cytokine secretion levels of CD8+ T cells. They also block cell cycle progression, induced apoptosis in CD8+ T cells. Image analysis of fluorescent labeled exosomes derived from three cell lines injected systemically into C57BL/6 mice revealed these exosomes primarily localize to the lungs. We further showed exosomes were mainly taken up by natural killer cells and macrophages in the lung. After long-term exposure to inject exosomes from MKN-45 cells, mice developed an immunosuppressive tumor microenvironment in the lung with increased frequency of effector memory CD4+ T and MDSC, decreased CD8+ T cell and NK frequency. This immune suppressive environment promotes gastric cancer lung metastasis. Lung metastasis sites developed after mice were exposed to exosomes isolated from all three gastric cancer cell lines when the mice were injected with MFC cells. Results suggest that exosomes derived from gastric cancer cells (especially MKN-45 and MKN-28) changed CD8+ T cell gene expression and cytokine secretion patterns to create an immunosuppressive condition for metastatic niche formation in the lung. Overall, this study provides new insights into how gastric cancer derived exosomes modulate the immune response to promote lung tumor metastasis.

scholarly journals T Lymphocytes and Testicular Immunity: A New Insight into Immune Regulation in Testes

2020 ◽  
Vol 22 (1) ◽  
pp. 57
Author(s):  
Jialei Gong ◽  
Qunxiong Zeng ◽  
Di Yu ◽  
Yong-Gang Duan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Tolerance ◽  
Cytotoxic T Cells ◽  
Γδ T Cells ◽  
Immune Privilege ◽  
T Cell Subsets ◽  
Infection And Inflammation ◽  
And Function

The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens, allowing for normal spermatogenesis. However, infection and inflammation of the male genital tract can break the immune tolerance and represent a significant cause of male infertility. Different T cell subsets have been identified in mammalian testes, which may be involved in the maintenance of immune tolerance and pathogenic immune responses in testicular infection and inflammation. We reviewed the evidence in the published literature on different T subtypes (regulatory T cells, helper T cells, cytotoxic T cells, γδ T cells, and natural killer T cells) in human and animal testes that support their regulatory roles in infertility and the orchitis pathology. While many in vitro studies have indicated the regulation potential of functional T cell subsets and their possible interaction with Sertoli cells, Leydig cells, and spermatogenesis, both under physiological and pathological processes, there have been no in situ studies to date. Nevertheless, the normal distribution and function of T cell subsets are essential for the immune privilege of the testes and intact spermatogenesis, and T cell-mediated immune response drives testicular inflammation. The distinct function of different T cell subsets in testicular homeostasis and the orchitis pathology suggests a considerable potential of targeting specific T cell subsets for therapies targeting chronic orchitis and immune infertility.

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).

Human Multiple Myeloma and Breast Cancer Cells Evade Immune Rejection Through Expression of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 6.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2942-2942
Author(s):  
Mathias Witzens-Harig ◽  
Dirk Hose ◽  
Simone Jünger ◽  
Christina Pfirschke ◽  
Nisit Khandelwal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Cell Adhesion Molecule ◽  
Cytotoxic T Cells ◽  
Cd8 T Cell ◽  
Related Cell

Abstract Abstract 2942 Tumor-specific cytotoxic T cells are common in tumor patients, but ineffectively react against autologous tumor cells. Here, we demonstrate in multiple myeloma and breast cancer that human tumor cells escape recognition by tumor-specific CD8+ T cells through carcinoembryonic antigen-related cell adhesion molecule-6 (CEACAM-6) expression. We demonstrate for the first time CEACAM-6 expression in primary and established myeloma and examined the effects of altered CEACAM expression on cytotoxic T cell activity and cytokine secretion against myeloma and breast cancer cells in vitro —, and in vivo, using a xenotransplant mouse model. Cytotoxic T cells from multiple myeloma patients reacted against myeloma antigens presented by dendritic cells, but not against autologous myeloma cells, which expressed CEACAM6. Gene knockdown or blocking of CEACAM6 on myeloma cells restored CD8+ T-cell reactivity against malignant plasma cells. SiRNA-mediated CEACAM6 knockdown or inhibition by specific mAbs also restored cytokine secretion, cytotoxic activity, and antigen-specific lysis of CEACAM6-positive breast cancer cells. Moreover, CEACAM-6 inhibition was a prerequisite for efficient treatment of xenotransplanted breast tumors by adoptive T cell transfer. CEACAM6 thus plays an important role in inhibiting CD8+ T-cell responses against hematological and epithelial human tumors. Therapeutic targeting of CEACAM6 may be a promising strategy for improving cancer immunotherapy. Disclosures: No relevant conflicts of interest to declare.

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.

scholarly journals CU06-1004-Induced Vascular Normalization Improves Immunotherapy by Modulating Tumor Microenvironment via Cytotoxic T Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Songyi Park ◽  
Ji Hoon Oh ◽  
Dong Jin Park ◽  
Haiying Zhang ◽  
Minyoung Noh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Synergistic Effects ◽  
Cytotoxic T Cells ◽  
Cell Activity ◽  
Immune Checkpoint Blockade ◽  
Combination Group ◽  
Potential Candidate ◽  
Immune Evasion Mechanism

Blocking the immune evasion mechanism of tumor cells has become an attractive means for treating cancers. However, the usage of a drug such as nivolumab (αPD-1), which blocks programmed cell death protein 1 (PD-1), turned out to be only effective against certain types of cancer. Especially, vascular abnormal structures of which deter delivery route by leakage and cause the poor perfusion were considered to be environment unfavorable to T cells and immune checkpoint blockade (ICB) delivery within the tumor microenvironment (TME). Herein, we report stabilization of tumor blood vessels by endothelial dysfunctional blocker CU06-1004, which modified the TME and showed synergistic effects with immunotherapy anti-PD-1 antibody. CU06-1004 combination therapy consistently prolonged the survival of tumor-bearing mice by decreasing tumor growth. T-cell infiltration increased in the tumors of the combination group, with cytotoxic CD8+ T cell activity within the tumor parenchyma upregulated compared with anti-PD-1 monotherapy. Tumor inhibition was associated with reduced hypoxia and reduced vessel density in the central region of the tumor. These effects correlated significantly with enhanced expression of IFN gamma and PD-L1 in tumors. Taken together, our findings suggest that CU06-1004 is a potential candidate drug capable of improving therapeutic efficacy of anti-PD-1 through beneficial changes in the TME.

scholarly journals Nature vs. Nurture: The Two Opposing Behaviors of Cytotoxic T Lymphocytes in the Tumor Microenvironment

2021 ◽  
Vol 22 (20) ◽  
pp. 11221
Author(s):  
Nagaja Capitani ◽  
Laura Patrussi ◽  
Cosima T. Baldari
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cytotoxic T Cells ◽  
Dual Nature ◽  
And Migration ◽  
Nature Vs Nurture

Similar to Janus, the two-faced god of Roman mythology, the tumor microenvironment operates two opposing and often conflicting activities, on the one hand fighting against tumor cells, while on the other hand, favoring their proliferation, survival and migration to other sites to establish metastases. In the tumor microenvironment, cytotoxic T cells—the specialized tumor-cell killers—also show this dual nature, operating their tumor-cell directed killing activities until they become exhausted and dysfunctional, a process promoted by cancer cells themselves. Here, we discuss the opposing activities of immune cells populating the tumor microenvironment in both cancer progression and anti-cancer responses, with a focus on cytotoxic T cells and on the molecular mechanisms responsible for the efficient suppression of their killing activities as a paradigm of the power of cancer cells to shape the microenvironment for their own survival and expansion.

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