scholarly journals Specific targeting of CD163+ TAMs mobilizes inflammatory monocytes and promotes T cell–mediated tumor regression

2019 ◽  
Vol 216 (10) ◽  
pp. 2394-2411 ◽  
Author(s):  
Anders Etzerodt ◽  
Kyriaki Tsalkitzi ◽  
Maciej Maniecki ◽  
William Damsky ◽  
Marcello Delfini ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Progression ◽  
Antitumor Immunity ◽  
Tumor Regression ◽  
Human Cancer ◽  
Experimental Models ◽  
Activated T Cells ◽  
Specific Targeting ◽  
Inflammatory Monocytes

Tumor-associated macrophages (TAMs) play critical roles in tumor progression but are also capable of contributing to antitumor immunity. Recent studies have revealed an unprecedented heterogeneity among TAMs in both human cancer and experimental models. Nevertheless, we still understand little about the contribution of different TAM subsets to tumor progression. Here, we demonstrate that CD163-expressing TAMs specifically maintain immune suppression in an experimental model of melanoma that is resistant to anti–PD-1 checkpoint therapy. Specific depletion of the CD163+ macrophages results in a massive infiltration of activated T cells and tumor regression. Importantly, the infiltration of cytotoxic T cells was accompanied by the mobilization of inflammatory monocytes that significantly contributed to tumor regression. Thus, the specific targeting of CD163+ TAMs reeducates the tumor immune microenvironment and promotes both myeloid and T cell–mediated antitumor immunity, illustrating the importance of selective targeting of tumor-associated myeloid cells in a therapeutic context.

scholarly journals CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alba Rodriguez-Garcia ◽  
Rachel C. Lynn ◽  
Mathilde Poussin ◽  
Monika A. Eiva ◽  
Lauren C. Shaw ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Progression ◽  
Antitumor Immunity ◽  
Folate Receptor ◽  
Tumor Associated Macrophages ◽  
Major Barrier ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

AbstractThe immunosuppressive tumor microenvironment (TME) represents a major barrier for effective immunotherapy. Tumor-associated macrophages (TAMs) are highly heterogeneous and plastic cell components of the TME which can either promote tumor progression (M2-like) or boost antitumor immunity (M1-like). Here, we demonstrate that a subset of TAMs that express folate receptor β (FRβ) possess an immunosuppressive M2-like profile. In syngeneic tumor mouse models, chimeric antigen receptor (CAR)-T cell-mediated selective elimination of FRβ+ TAMs in the TME results in an enrichment of pro-inflammatory monocytes, an influx of endogenous tumor-specific CD8+ T cells, delayed tumor progression, and prolonged survival. Preconditioning of the TME with FRβ-specific CAR-T cells also improves the effectiveness of tumor-directed anti-mesothelin CAR-T cells, while simultaneous co-administration of both CAR products does not. These results highlight the pro-tumor role of FRβ+ TAMs in the TME and the therapeutic implications of TAM-depleting agents as preparative adjuncts to conventional immunotherapies that directly target tumor antigens.

scholarly journals Type 17 immunity promotes the exhaustion of CD8+ T cells in cancer

2021 ◽  
Vol 9 (6) ◽  
pp. e002603
Author(s):  
Byung-Seok Kim ◽  
Da-Sol Kuen ◽  
Choong-Hyun Koh ◽  
Hyung-Don Kim ◽  
Seon Hee Chang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Progression ◽  
Adoptive Transfer ◽  
Human Cancer ◽  
Strong Positive Correlation ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Tc17 Cells

BackgroundMultiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) remain unclear.MethodsTo determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8+ TILs in Il17a−/− mice, Il17aCreR26DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4+ T cells or CD11b+Gr-1hi myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset.ResultsDepletion of CD4+ T cells promotes the exhaustion of CD8+ T cells with a concomitant increase in IL-17-producing CD8+ T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8+ T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103+KLRG1−IL-7Rαhi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1hiTim3+TOX+ terminally exhausted CD8+ T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8+ T cells and also delays tumor growth in vivo. Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8+ T cell exhaustion signature gene sets in multiple cancers.ConclusionIL-17-producing cells promote terminal exhaustion of CD8+ T cells and tumor progression in vivo, which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8+ T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.

scholarly journals Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer

Antibodies ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 25
Author(s):  
Violet Y. Tu ◽  
Asma Ayari ◽  
Roddy S. O’Connor
Keyword(s):  
T Cells ◽  
Lactic Acid ◽  
T Cell ◽  
Tumor Cells ◽  
Cell Biology ◽  
Redox Balance ◽  
Hematologic Malignancies ◽  
Activated T Cells ◽  
Unique Challenge ◽  
Cell Therapies

T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.

scholarly journals Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease

2021 ◽  
pp. annrheumdis-2020-219335
Author(s):  
Emma Garcia-Melchor ◽  
Giacomo Cafaro ◽  
Lucy MacDonald ◽  
Lindsay A N Crowe ◽  
Shatakshi Sood ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Migration ◽  
T Cell ◽  
Inflammatory Cytokines ◽  
T Cell Activation ◽  
Cell Activation ◽  
Conditioned Media ◽  
Tissue Remodelling ◽  
Activated T Cells ◽  
T Cell Migration

ObjectivesIncreasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation.MethodsT cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes.ResultsSignificant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte–T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio.ConclusionsInteraction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.

scholarly journals Oligomeric Procyanidins Interfere with Glycolysis of Activated T Cells. A Novel Mechanism for Inhibition of T Cell Function

Molecules ◽  
2015 ◽  
Vol 20 (10) ◽  
pp. 19014-19026 ◽  
Author(s):  
Masao Goto ◽  
Manabu Wakagi ◽  
Toshihiko Shoji ◽  
Yuko Takano-Ishikawa
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Activated T Cells ◽  
T Cell Function

scholarly journals Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

2006 ◽  
Vol 75 (3) ◽  
pp. 1154-1166 ◽  
Author(s):  
Laura H. Hogan ◽  
Dominic O. Co ◽  
Jozsef Karman ◽  
Erika Heninger ◽  
M. Suresh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bacterial Load ◽  
Granulomatous Inflammation ◽  
Cd8 T Cell ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

scholarly journals IL-36γ-armed oncolytic virus exerts superior efficacy through induction of potent adaptive antitumor immunity

2021 ◽  
Author(s):  
Min Yang ◽  
Esther Giehl ◽  
Chao Feng ◽  
Mathilde Feist ◽  
Hongqi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Therapeutic Efficacy ◽  
Oncolytic Virus ◽  
Antitumor Immunity ◽  
Human Cancer ◽  
Suppressor Cells ◽  
T Cell Differentiation ◽  
Effector Cells ◽  
Superior Efficacy ◽  
Vaccinia Viruses

AbstractIn this study, we aimed to apply the cytokine IL-36γ to cancer immunotherapy by constructing new oncolytic vaccinia viruses (OV) expressing interleukin-36γ (IL-36γ-OVs), leveraging unique synergism between OV and IL-36γ’s ability to promote antitumor adaptive immunity and modulate tumor microenvironment (TME). IL-36γ-OV had dramatic therapeutic efficacies in multiple murine tumor models, frequently leading to complete cancer eradication in large fractions of mice. Mechanistically, IL-36-γ-armed OV induced infiltration of lymphocytes and dendritic cells, decreased myeloid-derived suppressor cells and M2-like tumor-associated macrophages, and T cell differentiation into effector cells. Further study showed that IL-36γ-OV increased the number of tumor antigen-specific CD4+ and CD8+ T cells and the therapeutic efficacy depended on both CD8+ and CD4+ T cells. These results demonstrate that these IL36γ-armed OVs exert potent therapeutic efficacy mainly though antitumor immunity and they may hold great potential to advance treatment in human cancer patients.

scholarly journals Signals from OX40 regulate nuclear factor of activated T cells c1 and T cell helper 2 lineage commitment

2006 ◽  
Vol 103 (10) ◽  
pp. 3740-3745 ◽  
Author(s):  
T. So ◽  
J. Song ◽  
K. Sugie ◽  
A. Altman ◽  
M. Croft
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lineage Commitment ◽  
Nuclear Factor ◽  
Activated T Cells

scholarly journals Immunologically mediated regression of a murine lymphoma after treatment with anti-L3T4 antibody. A consequence of removing L3T4+ suppressor T cells from a host generating predominantly Lyt-2+ T cell-mediated immunity.

1988 ◽  
Vol 168 (6) ◽  
pp. 2193-2206 ◽  
Author(s):  
M Awwad ◽  
R J North
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Regression ◽  
Cell Mediated Immunity ◽  
Complete Regression ◽  
Suppressor T Cells ◽  
Antibody Treatment ◽  
P815 Mastocytoma ◽  
Thymectomized Mice

This study shows that intravenous injection of 1 mg of anti-L3T4 mAb (GK1.5) into thymectomized mice bearing the syngeneic L5178Y lymphoma results, after a delay of 2-3 d, in complete regression of this tumor and in long-term host survival. A flow cytofluorometric examination of the spleen cells of mAb-treated mice revealed that antibody treatment resulted in the elimination of greater than 98% of L3T4+ T cells, but had no effect on the Lyt-2+ T cells subset. Tumor regression was immunologically mediated, because L5178Y lymphoma cells were shown to be L3T4-, and regression of the tumor failed to occur in mice that had been lethally irradiated before anti-L3T4 mAb was given. Tumor regression was mediated by tumor-sensitized Lyt2+ T cells, as evidenced by the finding that treatment of tumor-bearing mice with anti-Lyt-2 mAb alone, or in combination with anti-L3T4 mAb, resulted in enhancement of tumor growth and a significant decrease in host survival time. Moreover, the spleens of mice whose tumors were undergoing regression in response to anti-L3T4 mAb treatment contained Lyt-2+ T cells capable, on passive transfer, of causing regression of a tumor in recipient mice. These results can be interpreted as showing that removal of tumor-induced L3T4+ suppressor T cells results in the release of Lyt-2+ effector T cells from suppression, and consequently in the generation of enough Lyt-2+ T cell-mediated immunity to cause tumor regression. This can only be achieved, however, if immunity to the tumor is mediated exclusively by Lyt-2+ T cells, as is the case for the L5178Y lymphoma. In the case of the P815 mastocytoma, treatment with anti-L3T4 mAb was without a therapeutic effect, and this was in keeping with the finding that immunity to this tumor is mediated by L3T4+, as well by Lyt-2+ T cells.

Sign in / Sign up

Export Citation Format

Share Document