Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade

Grabmeier‐Pfistershammer, Katharina; Stecher, Carmen; Zettl, Markus; Rosskopf, Sandra; Rieger, Armin; Zlabinger, Gerhard J.; Schmitz, Peter

doi:10.1016/j.clim.2017.09.002

Cited by 46 publications

(60 citation statements)

References 41 publications

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“…Our finding of PTPase preferences of PD-1 and BTLA is in general agreement with two recent studies (Celis-Gutierrez et al, 2019;Mintz et al, 2019). The distinct PTPase preferences might avoid the competition of PD-1 and BTLA, thus forming the basis for their functional synergy (Fourcade et al, 2012;Grabmeier-Pfistershammer et al, 2017;Zhao et al, 2016). The PD-1:SHP2 complex and BTLA:SHP1 complex can thus form independently and work in concert to suppress T cell activity.…”

Section: Discussionsupporting

confidence: 92%

PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

Hou

Fulzele

et al. 2020

Journal of Cell Biology

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Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debated. Here, we compared the abilities of BTLA and PD-1 to recruit effector molecules and to regulate T cell signaling. While PD-1 selectively recruited SHP2 over the stronger phosphatase SHP1, BTLA preferentially recruited SHP1 to more efficiently suppress T cell signaling. Contrary to the dominant view that PD-1 and BTLA signal exclusively through SHP1/2, we found that in SHP1/2 double-deficient primary T cells, PD-1 and BTLA still potently inhibited cell proliferation and cytokine production, albeit more transiently than in wild type T cells. Thus, PD-1 and BTLA can suppress T cell signaling through a mechanism independent of both SHP1 and SHP2.

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Section: Discussionsupporting

confidence: 92%

PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

Hou

Fulzele

et al. 2020

Journal of Cell Biology

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“…Notably, both HCV and BVDV belong to the Flaviviridae family. In addition, previous study on PD-1 blockade has confirmed the synergistic effect of PD-1 and other co-inhibitory molecules on T cells dysfunction during HIV (44) and HCV (45) infections. However, it is unclear whether PD-1 cooperates with other co-inhibitory molecules to regulate T cells dysfunction during BVDV infection, especially during NCP BVDV infection.…”

Section: Discussionmentioning

confidence: 66%

“…Tim-3 expression was upregulated on HIV-1 infected CD8 + T cells and associated with the inhibition of T cell proliferation and the impairment of ERK signaling (43). Blocking the co-inhibitory molecule Tim-3 with antibodies can enhance the proliferation of HIV-specific CD8 + T cells (44). CTLA-4 inhibits T cell proliferation and IL-2 production by suppressing TCR/CD28-induced ERK and JNK activation (45).…”

Section: Discussionmentioning

confidence: 99%

PD-1-Mediated PI3K/Akt/mTOR, Caspase 9/Caspase 3 and ERK Pathways Are Involved in Regulating the Apoptosis and Proliferation of CD4+ and CD8+ T Cells During BVDV Infection in vitro

Liu

et al. 2020

Front. Immunol.

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Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocyte (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection in vitro. However, the immunomodulatory effects of PD-1 pathway on major PBL subsets are unclear and their underlying molecular mechanisms need to be further studied. Therefore, in this study, we examined PD-1 expression in bovine PBL subsets after BVDV infection in vitro and analyzed the effects of PD-1 blockade on the apoptosis and proliferation of CD4 + and CD8 + T cells and expression of PD-1 downstream signaling molecules. The results showed that PD-1 expression was enhanced on CD4 + and CD8 + T cells, but not on CD21 + B cells after cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain KD) infection in vitro and PD-1 blockade significantly reduced the apoptosis of CD4 + and CD8 + T cells after these two strains infection. Remarkably, PD-1 blockade significantly increased the proliferation of CD4 + and CD8 + T cells after CP BVDV infection, but only significantly increased the proliferation of CD4 + T cells after NCP BVDV infection. In addition, we confirmed that PD-1-mediated PI3K/Akt/mTOR, caspase 9/caspase 3 and ERK pathways are involved in regulating the apoptosis and proliferation of CD4 + and CD8 + T cells during BVDV infection in vitro. Notably, ERK is involved in the regulation mechanism PD-1 mediated only when the cells are infected with CP BVDV. Our findings provide a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection.

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“…However, direct inhibition of CD8 + T cells by LAG-3 has also been described and distinct mechanisms have to be involved for such a function of LAG-3 ( 93 – 95 ). We have found that blocking LAG-3 alone or in combination with PD-1 on T cells stimulated with allogeneic DC or virus antigens had limited efficacy ( 49 , 50 ). In general, there are scarce data describing a robust effect of LAG-3 on human T cell responses in vitro .…”

Section: Lymphocyte Activation Gene-3 (Lag-3)mentioning

confidence: 99%

Not All Immune Checkpoints Are Created Equal

Linhares

Leitner

Grabmeier‐Pfistershammer

et al. 2018

Front. Immunol.

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128

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Antibodies that block T cell inhibition via the immune checkpoints CTLA-4 and PD-1 have revolutionized cancer therapy during the last 15 years. T cells express additional inhibitory surface receptors that are considered to have potential as targets in cancer immunotherapy. Antibodies against LAG-3 and TIM-3 are currently clinically tested to evaluate their effectiveness in patients suffering from advanced solid tumors or hematologic malignancies. In addition, blockade of the inhibitory BTLA receptors on human T cells may have potential to unleash T cells to effectively combat cancer cells. Much research on these immune checkpoints has focused on mouse models. The analysis of animals that lack individual inhibitory receptors has shed some light on the role of these molecules in regulating T cells, but also immune responses in general. There are current intensive efforts to gauge the efficacy of antibodies targeting these molecules called immune checkpoint inhibitors alone or in different combinations in preclinical models of cancer. Differences between mouse and human immunology warrant studies on human immune cells to appreciate the potential of individual pathways in enhancing T cell responses. Results from clinical studies are not only highlighting the great benefit of immune checkpoint inhibitors for treating cancer but also yield precious information on their role in regulating T cells and other cells of the immune system. However, despite the clinical relevance of CTLA-4 and PD-1 and the high potential of the emerging immune checkpoints, there are still substantial gaps in our understanding of the biology of these molecules, which might prevent the full realization of their therapeutic potential. This review addresses PD-1, CTLA-4, BTLA, LAG-3, and TIM-3, which are considered major inhibitory immune checkpoints expressed on T cells. It provides summaries of our current conception of the role of these molecules in regulating T cell responses, and discussions about major ambiguities and gaps in our knowledge. We emphasize that each of these molecules harbors unique properties that set it apart from the others. Their distinct functional profiles should be taken into account in therapeutic strategies that aim to exploit these pathways to enhance immune responses to combat cancer.

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Antibodies targeting BTLA or TIM-3 enhance HIV-1 specific T cell responses in combination with PD-1 blockade

Cited by 46 publications

References 41 publications

PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

PD-1-Mediated PI3K/Akt/mTOR, Caspase 9/Caspase 3 and ERK Pathways Are Involved in Regulating the Apoptosis and Proliferation of CD4+ and CD8+ T Cells During BVDV Infection in vitro

Not All Immune Checkpoints Are Created Equal

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