FOXD3 Regulates VISTA Expression in Melanoma

Rosenbaum, Sheera; Knecht, Meghan; Mollaee, Mehri; Zhong, Zhijiu; Erkes, Dan A.; McCue, Peter A.; Chervoneva, Inna; Berger, Adam C.; Lo, Jennifer A.; Fisher, David E.; Gershenwald, Jeffrey E.; Davies, Michael A.; Purwin, Timothy J.; Aplin, Andrew E.

doi:10.1016/j.celrep.2019.12.036

Cited by 53 publications

(39 citation statements)

References 55 publications

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“…Rosenbaum et al observed that VISTA is expressed in melanoma patient samples and cell lines. Furthermore, tumor cellspecific expression of VISTA, which is regulated by factor forkhead box D3 (FOXD3), promotes tumor onset and enhances PD-L1 expression on tumorinfiltrating macrophages in vivo and is associated with increased intra-tumoral T regulatory cells [19]. There is some evidence that PD-L1/VISTA expression correlates with melanoma survival [19,32,33].…”

Section: Melanomamentioning

confidence: 99%

VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy

et al. 2020

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VISTA (V-domain immunoglobulin suppressor of T cell activation) is a well-established immune regulatory receptor. However, pre-clinical investigations indicated more complicated influences of VISTA on cancer immunity than previously recognized. Here, we review the current knowledge on the therapeutic phenotypes and molecular mechanisms that underlie the contradictory roles of VISTA in checking anti-cancer immune responses. Furthermore, we highlight the potential indeterminacy of VISTA-targeted strategies in cancer immunotherapy, with in silico analyses. In fact, VISTA functions like a homeostatic regulator that actively normalizes immune responses. Thus, the regulatory role of VISTA in anti-cancer immunity remains to be fully elucidated.

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Section: Melanomamentioning

confidence: 99%

VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy

et al. 2020

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“…TAMs express high levels of V-domain Ig suppressor of T cell activation (VISTA), another negative immune checkpoint, which is correlated with resistance to immunotherapy [ 154 , 155 ]. VISTA, associated with a significant decrease of survival in primary melanomas, in vivo, promotes a protumoral microenvironment mediated by upregulation of Tregs’ levels and PDL-1 expression on macrophages’ surface [ 155 , 156 , 157 , 158 ].…”

Section: Tme Implications In Drug Resistance For Melanomamentioning

confidence: 99%

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

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et al. 2020

Cancers

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Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase kinase (MEK), v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immunotherapy. However, despite the progress made in the melanoma treatment, primary and/or acquired drug resistance remains an unresolved problem. The molecular dynamics that promote this phenomenon are very complex but several studies have shown that the tumor microenvironment (TME) plays, certainly, a key role. In this review, we will describe the new melanoma treatment approaches and we will analyze the mechanisms by which TME promotes resistance to targeted therapy and immunotherapy.

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“…V-domain Immunoglobulin Suppressor of T cell activation (VISTA; alias PD-1H, Gi24, DD1α, Vsir, or Dies1) is an inhibitory molecule expressed on many cell types including DCs, other myeloid cells, CD4 + and CD8 + T cells as well as tumor cells [ 516 , 517 , 518 ]. VISTA acts as both, receptor and ligand [ 519 ].…”

Section: Dcs Orchestrate T Cell-driven Immunitymentioning

confidence: 99%

“…Further, VISTA was upregulated by p53 activity contributing to the clearance of dead cells by boosting phagocyte functions [ 518 ]. Thus, VISTA might be important on different cell types including apoptotic cells, phagocytes and T cells, to retain unresponsiveness to antigens derived from dead cells and consequently for the immunological silencing [ 517 , 521 ]. However, the very same mechanisms might be hijacked by cancer cells to escape immune surveillance [ 517 , 521 ].…”

Section: Dcs Orchestrate T Cell-driven Immunitymentioning

confidence: 99%

“…Thus, VISTA might be important on different cell types including apoptotic cells, phagocytes and T cells, to retain unresponsiveness to antigens derived from dead cells and consequently for the immunological silencing [ 517 , 521 ]. However, the very same mechanisms might be hijacked by cancer cells to escape immune surveillance [ 517 , 521 ]. Thus, VISTA blockade in the tumor microenvironment may change the anti-inflammatory context during uptake of VISTA + tumor cells and thereby impeding the subsequent suppression of T cell immune responses induced by VISTA + phagocytes.…”

Section: Dcs Orchestrate T Cell-driven Immunitymentioning

confidence: 99%

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Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

et al. 2020

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The onset of checkpoint inhibition revolutionized the treatment of cancer. However, studies from the last decade suggested that the sole enhancement of T cell functionality might not suffice to fight malignancies in all individuals. Dendritic cells (DCs) are not only part of the innate immune system, but also generals of adaptive immunity and they orchestrate the de novo induction of tolerogenic and immunogenic T cell responses. Thus, combinatorial approaches addressing DCs and T cells in parallel represent an attractive strategy to achieve higher response rates across patients. However, this requires profound knowledge about the dynamic interplay of DCs, T cells, other immune and tumor cells. Here, we summarize the DC subsets present in mice and men and highlight conserved and divergent characteristics between different subsets and species. Thereby, we supply a resource of the molecular players involved in key functional features of DCs ranging from their sentinel function, the translation of the sensed environment at the DC:T cell interface to the resulting specialized T cell effector modules, as well as the influence of the tumor microenvironment on the DC function. As of today, mostly monocyte derived dendritic cells (moDCs) are used in autologous cell therapies after tumor antigen loading. While showing encouraging results in a fraction of patients, the overall clinical response rate is still not optimal. By disentangling the general aspects of DC biology, we provide rationales for the design of next generation DC vaccines enabling to exploit and manipulate the described pathways for the purpose of cancer immunotherapy in vivo. Finally, we discuss how DC-based vaccines might synergize with checkpoint inhibition in the treatment of malignant diseases.

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FOXD3 Regulates VISTA Expression in Melanoma

Abstract: Highlights d VISTA is heterogeneously expressed on melanoma cells d VISTA expression promotes tumor onset and alters the immune microenvironment d FOXD3 suppresses the expression of VISTA d BRAF/MEK inhibitor treatment reduces levels of VISTA

Cited by 53 publications

References 55 publications

VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy

VISTA: an immune regulatory protein checking tumor and immune cells in cancer immunotherapy

Tumor Microenvironment: Implications in Melanoma Resistance to Targeted Therapy and Immunotherapy

Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

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