scholarly journals Evolution of immune escape mechanisms in the progression from preinvasive to invasive human lung adenocarcinoma

2020 ◽  
Author(s):  
Nasser K. Altorki ◽  
Alain C. Borczuk ◽  
Vivek Mittal ◽  
Olivier Elemento ◽  
Timothy E. McGraw
Keyword(s):  
T Cells ◽  
Minimally Invasive ◽  
Lung Adenocarcinoma ◽  
Disease Progression ◽  
Immune Escape ◽  
Cytotoxic T Cells ◽  
Treg Cells ◽  
Normal Lung ◽  
Ct Density ◽  
Immune Escape Mechanisms

SummaryThe tumor microenvironment (TME) of lung adenocarcinoma (LUAD) precursor lesions has not been described. We interrogated by multiplex immunofluorescence the TME of preinvasive and invasive Stage 1A LUADs selected by computer tomography (CT) scan-density. Pure non-solid (p-NS) CT density nodules are preinvasive/minimally invasive, whereas solid CT density nodules are frankly invasive cancers. Our data reveal an intensely immune-suppressive immune TME in p-NS tumors characterized by an increase in Treg cells and a decrease in cytotoxic T cells relative to normal lung. The TME of the solid tumor group, more advanced lesions than the p-NS yet still early in disease development, were increasingly more immune-suppressive. Provocatively, there was a further increase in both Treg cells and cytotoxic T cells, establishing a nascent albeit ineffective anti-tumor immune response in transition from preinvasive p-NS to invasive solid tumors. Regulatory T cells play a dominant role throughout progression, while additional immune evasive mechanisms are employed at different stages of disease progression, including T cell exclusion from cancer cell nests early and activation of immune checkpoints later. Our study establishes that different immune-targeted strategies are required to intercept disease progression at these two distinct early points of lung cancer development.Statement of SignificanceUsing multiplexed IF, we compared the cellular composition and activation state of the tumor immune microenvironment between pre/minimally invasive and frankly invasive adenocarcinoma. We found a progressive increase in immunosuppressive mechanisms in association with disease progression suggesting that Interception strategies should be specifically tailored based on underlying immune escape mechanisms

scholarly journals Galectin-3 as a new negative checkpoint of the immune response is the key target for effective immunotherapy against prostate cancer

2019 ◽  
Author(s):  
Carolina Tiraboschi ◽  
Lucas Gentilini ◽  
Felipe M. Jaworski ◽  
Enrique Corapi ◽  
Carla Velazquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Immune Escape ◽  
Cytotoxic T Cells ◽  
Combined Treatment ◽  
Clinical Samples ◽  
Major Health Problem ◽  
Galectin 3 ◽  
Prostate Tumor Cells ◽  
Immune Escape Mechanisms

AbstractProstate cancer (PCa) is a major health problem worldwide. Taxol derivatives–based chemotherapies or immunotherapies are usually proposed depending on the symptomatic status. In the case of immunotherapy, tumors develop robust immune escape mechanisms that abolish any protective response. However, Docetaxel has been shown to enhance the effectiveness of immunotherapy in a variety of cancers, but to date, the mechanism is still unknown. Herein, we showed first that Galectin-3 (Gal-3) expressed by prostate tumor cells is the principal immunological checkpoint responsible of the failure of immunotherapy; and that Docetaxel leads to the inhibition of Gal-3 expression in PCa cells as well as in clinical samples of mCRPC patients promoting a Th1 response. We thus optimized a prostate cancer animal model that undergoes surgical resection of the tumor like prostatectomy to mimic what is usually performed in patients. More importantly, using low and nontoxic doses of taxane prior to immunotherapy, we were able to directly impact the activation and proliferation of CD8+ cytotoxic T cells through reducing the number of CD8+CD122+CD28-T cells and highly control tumor recurrence. Thus, Gal-3 expression by PCa cells is a key inhibitor for the success of immunotherapy, and low doses of Docetaxel with noncytotoxic effect on leukocyte survival should be used prior to vaccination for all PCa patients. This combined treatment sequence right after surgery would promote the preconditioning of the tumor microenvironment, allowing for effective anti-tumor immunotherapy and can be transferred rapidly to clinical therapeutic protocols.

EXTH-72. TRANSLATIONAL INVESTIGATION OF TD139 FOR THE TREATMENT OF HIGH-GRADE MENINGIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi179-vi180
Author(s):  
Connor Stephenson ◽  
Katie Ross ◽  
William Vandergrift III ◽  
Abhay Varma ◽  
Bruce Frankel ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cytotoxic T Cells ◽  
Transglutaminase 2 ◽  
Treg Cells ◽  
Orphan Receptor ◽  
High Grade ◽  
Ki 67 ◽  
Western Blots

Abstract BACKGROUND High-Grade Meningioma (HGM), such as atypical and anaplastic meningiomas, represent a subgroup of meningiomas with histologic and clinical features suggesting aggressive behavior with a penchant for recurrence, even after surgical resection. Here, we postulate that high levels of Galectin-3 (Gal-3) affect the cellular composition and are at the root of the profoundly immunosuppressive tumor microenvironment of HGM. Our study aimed to validate the effect of the Gal-3 inhibitor (TD139) in in vivo. METHODS In vivo MGS2 murine models of HGM were utilized to assess efficacy of treatment with TD139 via intravenous injection. We used ELISA spot, RT-PCR and western blots techniques. MRI and immunohistochemistry -staining methods were used to detect tumor growth in in vivo following TD139 treatments. RESULTS Our results demonstrated a significantly elevated level of Gal-3 in both HGM tissue and serum when compared to non-tumor patients. Furthermore, Epithelial membrane antigen, Ki-67, and Transglutaminase 2 were highly expressed in HGM, whereas the number of observed cytotoxic T-cells in HGM was markedly decreased. When human PBMCs were activated with anti-CD3 (1µg/ml) and anti-CD28 (2µg/ml) antibodies and treated with recombinant Gal-3 protein (500ng/ml) for 96hr, we found reduced expression of T-Box Transcription Factor 21 and RAR Related Orphan Receptor C mRNA with concurrent upregulated expression of GATA Binding protein 3 and Forkhead box P3 mRNA. These findings support the concept that Gal-3 skews the differentiation of CD4+ T cells towards Th2 and Treg cells. In vivo treatment of TD139 (1mg/kg per day for 14 days) showed significant decrease (∼35%) in MGS2 tumor growth in orthotopic allograft model (at Day 41) and increased survival via multiple mechanism. Additionally, we observed an upregulation of CD38 (M1 macrophages) and CD8+ T cells in treated cells. CONCLUSIONS These findings suggest that TD139 may be an effective approach in the treatment of HGM patients.

scholarly journals Blockade of Lactate Dehydrogenase-A (LDH-A) Improves Efficacy of Anti-Programmed Cell Death-1 (PD-1) Therapy in Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 450 ◽  
Author(s):  
Saeed Daneshmandi ◽  
Barbara Wegiel ◽  
Pankaj Seth
Keyword(s):  
T Cells ◽  
Cell Death ◽  
Lactate Dehydrogenase ◽  
Programmed Cell Death ◽  
Immune Cell ◽  
Cytotoxic T Cells ◽  
Treg Cells ◽  
Interferon Γ ◽  
Mitochondrial Activity ◽  
Small Subset

Immunotherapy is a curable treatment for certain cancers, but it is still only effective in a small subset of patients. We have recently reported that programmed cell death protein-1 (PD-1) ligand (PD-L1) expression is regulated by lactate present at high levels in the tumor microenvironment (TME). We hypothesized that the efficacy of anti-PD-1 treatment can be improved by blocking the lactate-generating enzyme, lactate dehydrogenase-A (LDH-A). Anti-PD-1 treatment of mice harboring LDH-A deficient B16-F10 melanoma tumors led to an increase in anti-tumor immune responses compared to mice implanted with tumors expressing LDH-A. Specifically, we observed heightened infiltration of natural killer (NK) cells and CD8+ cytotoxic T cells in the LDH-A deficient tumors. These infiltrated cytotoxic cells had an elevated production of interferon-γ (IFN-γ) and granzyme B. Mechanistically, CD8+ T cells isolated from the TME of LDH-A deficient B16-F10 melanoma tumors and treated with anti-PD-1 showed enhanced mitochondrial activity and increased reactive oxygen species (ROS) levels. Moreover, infiltration of T regulatory (Treg) cells was diminished in LDH-A deficient tumors treated with anti-PD-1. These altered immune cell profiles were clinically relevant as they were accompanied by significantly reduced tumor growth. Our study suggests that blocking LDH-A in the tumor might improve the efficacy of anti-PD-1 therapy.

scholarly journals Harnessing PD-L1-specific cytotoxic T cells for anti-leukemia immunotherapy to defeat mechanisms of immune escape mediated by the PD-1 pathway

Leukemia ◽  
2013 ◽  
Vol 28 (1) ◽  
pp. 236-238 ◽  
Author(s):  
S M Ahmad ◽  
S K Larsen ◽  
I M Svane ◽  
M H Andersen
Keyword(s):  
T Cells ◽  
Immune Escape ◽  
Cytotoxic T Cells

Soluble IL2R (CD25), IL10 and PDL1 May Control T Cell Activation in Chronic Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4252-4252
Author(s):  
Lisa Christiansson ◽  
Camilla Lindqvist ◽  
Thomas H Tötterman ◽  
Bengt Simonsson ◽  
Ulla Olsson-Strömberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Immune Escape ◽  
Death Receptor ◽  
T Cell Proliferation ◽  
Programmed Death ◽  
Immune Escape Mechanisms

Abstract Abstract 4252 Cancer patients are known to have an impaired anti-tumor immune response because of various immune escape mechanisms exerted by the tumor cells. These mechanisms involve release of soluble molecules and expression of membrane-bound proteins inhibiting different arms of the anti-tumor immune responses. The immune escape mechanisms seen in cancer patients complicate the use of immunotherapy, such as tumor vaccines and adoptive T cell transfer. The aim of our study was to investigate the presence of IL10, soluble IL2R (sIL2R; CD25) and programmed death receptor ligand 1 (PDL1) in patients with chronic myeloid leukemia (CML) and to study their role as T cell inhibitors. IL10, sIL2R and PDL1 are all known immune inhibitory molecules. IL10 is a secreted molecule that has various suppressive effects on many different immune cells. sIL2R binds IL2 efficiently and may thereby prevent the binding of IL2 to IL2R on T cells, an interaction that is necessary for proliferation and maintenance of tumor-specific T cells. PDL1-expressing tumor cells can bind programmed death receptor 1 (PD1) on T cells. This interaction can induce apoptosis in the T cells. In this study, we used cytometric bead array, ELISA and multicolor flow cytometry to screen CML patients and healthy controls for the presence of IL10, sIL2R and PDL1 in blood. Further, Alamar Blue TM assay and IFNγ detection by flow cytometry were used to investigate T cell proliferation and activation in the presence of the inhibitors. We found that the levels of IL10 and sIL2R were increased in CML patient plasma compared to the levels in healthy control subjects. The level of sIL2R in a subgroup of patients was four-fold higher than the mean level of healthy controls. Patient T cells stimulated with various strong T cell stimuli including CML-specific peptides failed to respond to stimuli as measured by flow cytometric detection of the cytotoxic T cell activation marker IFNγ, indicating that these T cells might be anergic. In vitro studies on T cells from healthy donors showed that both IL10 and sIL2R have the ability to inhibit T cell proliferation. Half of the CML patients had a PDL1 expression on the CD34 cell population raging from 1-36%. PDL1 may, hence, be involved in T cell control in CML. Taken together, our results show that T cells from CML patients fail to respond to stimuli and that these T cells may be controlled by the high levels of IL10, sIL2R and PDL1 seen in the patients. Screening for these inhibitors may aid selection of patients considered for immunotherapy. Disclosures: Simonsson: Novartis: Consultancy, Honoraria, Research Funding, Sponsor; BMS: Consultancy, Honoraria, Research Funding, Sponsor; SCHERING-PLOUGH: Sponsor. Olsson-Strömberg:BMS: Honoraria.

Low TWEAK expression indicates poor survival and is correlated with sparse TIICs in lung adenocarcinoma (LUAD).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21017-e21017
Author(s):  
Jinchun Wu ◽  
Xianyu Liu ◽  
Yanhua Mou ◽  
Shan Zeng ◽  
Jin Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Lung Adenocarcinoma ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Immune Escape ◽  
Underlying Mechanism ◽  
Memory Cd8 T Cells ◽  
Kaplan Meier ◽  
Kaplan Meier Plotter

e21017 Background: Lung adenocarcinoma (LUAD) occupies the most of non-small cell lung cancer (NSCLC) and shows promising response to PD-1 immunotherapy, but immune escape will cause treatment failure indicating poor prognosis. TWEAK (Tumor necrosis factor-related weak inducer of apoptosis, also known as TNFSF12) combining with its receptor FN14 (fibroblast growth factor–inducible 14) mediates crucial innate and adaptive immune pathways to promote the progression of multiple autoimmune diseases. So we assumed that TWEAK is a prognostic predictor and related with tumor-infiltrating immune cells (TIICs) in LUAD. Methods: TWEAK expression of LUAD was primarily investigated in The Cancer Immunome Atlas (TCIA) and then validated in Tumor Immune Estimation Resource (TIMER) databases. We assessed the effect of TWEAK on the survival via the Kaplan-Meier plotter, GEPIA2 (gene expression profiling interactive analysis) and PrognoScan databases. The relation between TWEAK and TIICs was explored in TIMER and TCIA, as well as the correlation of TWEAK and FN14 was analyzed in TIMER and GEPIA2. Results: Low TWEAK expression was significantly associated with poor relapse-free survival (RFS) (HR = 0.62, 95% CI = 0.4~0.97, logrank P = 0.035) and overall survival (OS) (HR = 0.61, 95% CI = 0.46~0.83, logrank P = 0.0012) in LUAD from Kaplan-Meier plotter. Similar impacts of TWEAK on the survival were validated in GEPIA2 and four independent cohorts from PrognoScan (jacob-00182-CANDF, GSE13213, jacob-00182-MSK and GSE31210). Moreover, reduced TWEAK expression was closely related with the paucity of TIICs which contributed to poor OS, including central memory CD8 T cells, plasmacytoid dendritic cells, activated CD8 T cells, monocytes, T follicular helper cells, immature B cells and eosinophils. In addition, TWEAK expression was positively related with the expression level of FN14 in both GEPIA2(R = 0.13, P= 0.0031) and TIMER (partial.cor = 0.212, P= 2.04e-06). Conclusions: Low TWEAK expression maybe indicate poor prognosis in LUAD, and correlated with the impaired infiltration of immune cells in the tumor region. The defective TWEAK/FN14 pathway possibly accounts for these observations, but the underlying mechanism needs to be further explored.

Cytotoxic T cells—protection from disease progression—protection from infection

1996 ◽  
Vol 51 (1-2) ◽  
pp. 125-128 ◽  
Author(s):  
Frances Gotch ◽  
Awen Gallimore ◽  
Andrew McMichael
Keyword(s):  
T Cells ◽  
Disease Progression ◽  
Cytotoxic T Cells

scholarly journals ­ Apatinib combined with PD-L1 blockade synergistically enhances antitumor immune responses and promotes HEV formation in gastric cancer

2021 ◽  
Author(s):  
Yu Zhang ◽  
Fei Wang ◽  
Hao-ran Sun ◽  
Ya-kai Huang ◽  
Jian-peng Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Combination Therapy ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Antibody Therapy ◽  
Treg Cells ◽  
Cytotoxic T Cell ◽  
Immunocompetent Mice

Abstract Purpose Apatinib, an antiangiogenic drug, has showed beneficial effects only in a fraction of advanced gastric cancer (GC) patients. Given the recent success of immunotherapies, combination of apatinib with immune checkpoint inhibitor may provide sustained and potent antitumor responses. Methods Immunocompetent mice with subcutaneous MFC tumors grown were given combination of apatinib and anti-PD-L1 antibody therapy. GC tissues from patients undergoing curative resection in China were collected, and the density of HEVs, MSI status and tumor-infiltrated lymphocytes were analyzed by immunohistochemical staining. Results Combined apatinib and PD-L1 blockade therapy synergistically delayed tumor growth and increased survival in MFC-bearing immunocompetent mice. The combination therapy promoted antitumor immunity by increasing the ratio of CD8+ cytotoxic T cells to Foxp3+ Treg cells, the accumulation of CD20+ B cells and the Th1/Th2 cytokine ratio (IFN-γ/IL-10). The combination therapy induced the formation of HEVs through activation of LTβR signaling, thus promoting CD8+ cytotoxic T cell and CD20+ B cell infiltration in tumors. In clinical GC samples, the density of HEVs positively correlated with the intratumoral infiltration of CD8+ cytotoxic T cells and CD20+ B cells. MSI-high GC showed a higher density of HEVs, CD8+ cytotoxic T cells and CD20+ B cells than MSS/MSI-low GC. GC patients with high densities of HEVs, CD8+ cytotoxic T cells and CD20+ B cells had an improved prognosis with superior overall survival. Conclusion Combining apatinib with PD-L1 blockade treatment synergistically enhances antitumor immune responses and promotes HEV formation in GC.

scholarly journals High IKZF2 Expression in Malignant T cells Promotes Disease Progression in Cutaneous T cell Lymphoma

2021 ◽  
Author(s):  
Bufang Xu ◽  
Fengjie Liu ◽  
Yumei Gao ◽  
Jingru Sun ◽  
Yingyi Li ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Malignant Cell ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Tumor Immune Escape ◽  
Malignant T Cells

Cutaneous T cell lymphoma is a generally indolent disease derived from skin-homing mature T cells. However, in advanced stages, CTCL may manifest as aggressive clinical behavior and lead to a poor prognosis. The mechanism of disease progression in CTCL remains unknown. Here, with a large clinical cohort, we identified that IKZF2, an essential transcription factor during T cell development and differentiation, showed stage-dependent overexpression in the malignant T cells in MF lesions. IKZF2 is specifically over-expressed in advanced-stage MF lesions, correlates with poor patient prognosis. Mechanistically, IKZF2 overexpression promotes CTCL progression via inhibiting malignant cell apoptosis and may contribute to tumor immune escape by downregulating MHC-II molecules and up-regulating the production of anti-inflammatory cytokine IL-10 by malignant T cells. These results demonstrate the important role of IKZF2 in high-risk CTCL and pave the way for future targeted therapy.

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