T Cell Tuning for Tumour Therapy: Enhancing Effector Function and Memory Potential of Therapeutic T cells

2015 ◽  
Vol 15 (3) ◽  
pp. 289-299
Author(s):  
Mathias Zech ◽  
Pedro Velica ◽  
Hans Stauss
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector Function ◽  
Tumour Therapy

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling

2021 ◽  
Author(s):  
Juanjuan Yuan ◽  
Ting Cai ◽  
Xiaojun Zheng ◽  
Yangzi Ren ◽  
Jingwen Qi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Metabolic Regulation ◽  
Cholesterol Metabolism ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Cell Receptor ◽  
Suppressive Effect ◽  
Effector Function

AbstractMetabolic regulation has been proven to play a critical role in T cell antitumor immunity. However, cholesterol metabolism as a key component of this regulation remains largely unexplored. Herein, we found that the low-density lipoprotein receptor (LDLR), which has been previously identified as a transporter for cholesterol, plays a pivotal role in regulating CD8+ T cell antitumor activity. Besides the involvement of cholesterol uptake which is mediated by LDLR in T cell priming and clonal expansion, we also found a non-canonical function of LDLR in CD8+ T cells: LDLR interacts with the T-cell receptor (TCR) complex and regulates TCR recycling and signaling, thus facilitating the effector function of cytotoxic T-lymphocytes (CTLs). Furthermore, we found that the tumor microenvironment (TME) downregulates CD8+ T cell LDLR level and TCR signaling via tumor cell-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) which binds to LDLR and prevents the recycling of LDLR and TCR to the plasma membrane thus inhibits the effector function of CTLs. Moreover, genetic deletion or pharmacological inhibition of PCSK9 in tumor cells can enhance the antitumor activity of CD8+ T cells by alleviating the suppressive effect on CD8+ T cells and consequently inhibit tumor progression. While previously established as a hypercholesterolemia target, this study highlights PCSK9/LDLR as a potential target for cancer immunotherapy as well.

scholarly journals Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Weiqin Jiang ◽  
Yinjun He ◽  
Wenguang He ◽  
Guosheng Wu ◽  
Xile Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Burden ◽  
Effector Function ◽  
T Cell Exhaustion ◽  
Immune Microenvironment ◽  
Cell Exhaustion ◽  
Combination Strategies ◽  
Cell Pool ◽  
Tumor Immune Microenvironment

Tumor-specific CD8+T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8+T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8+T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.

scholarly journals Antigen-independent activation of naive and memory resting T cells by a cytokine combination.

1994 ◽  
Vol 180 (3) ◽  
pp. 1159-1164 ◽  
Author(s):  
D Unutmaz ◽  
P Pileri ◽  
S Abrignani
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Interleukin 2 ◽  
Effector Function ◽  
Necrosis Factor Alpha ◽  
Naive T Cells ◽  
Naïve T Cells

We investigated whether human resting T cells could be activated to proliferate and display effector function in the absence of T cell receptor occupancy. We report that combination of interleukin 2 (IL-2), tumor necrosis factor alpha, and IL-6 activated highly purified naive (CD45RA+) and memory (CD45RO+) resting CD4+ T cells to proliferate. Under this condition, memory resting T cells could also display effector function as measured by lymphokine synthesis and help for immunoglobulin production by B cells. This novel Ag-independent pathway of T cell activation may play an important role in vivo in recruiting effector T cells at the site of immune response and in maintaining the clonal size of memory T cells in the absence of antigenic stimulation. Moreover, cytokines can induce proliferation of naive T cells without switch to memory phenotype and this may help the maintenance of the peripheral pool of naive T cells.

scholarly journals Priming of Antiviral CD8 T Cells without Effector Function by a Persistently Replicating Hepatitis C-Like Virus

2020 ◽  
Vol 94 (10) ◽  
Author(s):  
Alex S. Hartlage ◽  
Christopher M. Walker ◽  
Amit Kapoor
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Animal Models ◽  
Cd8 T Cells ◽  
Persistent Infection ◽  
Cd8 T Cell ◽  
Effector Function ◽  
Viral Escape

ABSTRACT Immune-competent animal models for the hepatitis C virus (HCV) are nonexistent, impeding studies of host-virus interactions and vaccine development. Experimental infection of laboratory rats with a rodent hepacivirus isolated from Rattus norvegicus (RHV) is a promising surrogate model due to its recapitulation of HCV-like chronicity. However, several aspects of rat RHV infection remain unclear, for instance, how RHV evades host adaptive immunity to establish persistent infection. Here, we analyzed the induction, differentiation, and functionality of RHV-specific CD8 T cell responses that are essential for protection against viral persistence. Virus-specific CD8 T cells targeting dominant and subdominant major histocompatibility complex class I epitopes proliferated considerably in liver after RHV infection. These populations endured long term yet never acquired antiviral effector functions or selected for viral escape mutations. This was accompanied by the persistent upregulation of programmed cell death-1 and absent memory cell formation, consistent with a dysfunctional phenotype. Remarkably, transient suppression of RHV viremia with a direct-acting antiviral led to the priming of CD8 T cells with partial effector function, driving the selection of a viral escape variant. These data demonstrate an intrinsic abnormality within CD8 T cells primed by rat RHV infection, an effect that is governed at least partially by the magnitude of early virus replication. Thus, this model could be useful in investigating mechanisms of CD8 T cell subversion, leading to the persistence of hepatotropic pathogens such as HCV. IMPORTANCE Development of vaccines against hepatitis C virus (HCV), a major cause of cirrhosis and cancer, has been stymied by a lack of animal models. The recent discovery of an HCV-like rodent hepacivirus (RHV) enabled the development of such a model in rats. This platform recapitulates HCV hepatotropism and viral chronicity necessary for vaccine testing. Currently, there are few descriptions of RHV-specific responses and why they fail to prevent persistent infection in this model. Here, we show that RHV-specific CD8 T cells, while induced early at high magnitude, do not develop into functional effectors capable of controlling virus. This defect was partially alleviated by short-term treatment with an HCV antiviral. Thus, like HCV, RHV triggers dysfunction of virus-specific CD8 T cells that are vital for infection resolution. Additional study of this evasion strategy and how to mitigate it could enhance our understanding of hepatotropic viral infections and lead to improved vaccines and therapeutics.

scholarly journals Disparate Primary and Secondary Allospecific CD8+ T Cell Cytolytic Effector Function in the Presence or Absence of Host CD4+ T Cells

2007 ◽  
Vol 179 (1) ◽  
pp. 80-88 ◽  
Author(s):  
Phillip H. Horne ◽  
Mitchel A. Koester ◽  
Kartika Jayashankar ◽  
Keri E. Lunsford ◽  
Heather L. Dziema ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Effector Function
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