Up-Regulation of PD-L1, IDO, and Tregs in the Melanoma Tumor Microenvironment Is Driven by CD8+ T Cells

By S. Spranger, R. Spaapen, Y. Zha, Jason B. Williams, Yuru Meng, T. T. Ha, T. Gajewski. Science Translational Medicine, 2013

1,648 citations recorded by the source corpus.

CD8+ T cells induce immunosuppressive mechanisms in the tumor microenvironment. The Great Escape One of the long-standing questions in cancer biology is how tumors evade the patrolling immune response. Many potential explanations have been proposed, including that the tumor itself suppresses the immune response. Indeed, some of the most promising new immunotherapies work by blocking inhibitory molecules, which enhances immune activity against the tumor. Now, Spranger et al. show that immunosuppressive mechanisms in the tumor may involve negative feedback loops dependent on an infiltrating immune response. The authors noticed that even tumors that are infiltrated with CD8+ T cells are not rejected and that this correlated with expression of three types of immunosuppressives: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and regulatory T cells. Mechanistic studies in mice suggested that CD8+ T cells were required to be in the tumor microenvironment for the up-regulation of these immunosuppressives. Extending these studies to the clinic, patients with inflammatory tumor infiltrates will thus be more likely to benefit from immune checkpoint therapies. Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8+ T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell–inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3+ regulatory T cells (Tregs), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8+ T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of Tregs, in the tumor microenvironment depended on the presence of CD8+ T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell–inflamed tumor microenvironment.

Subfields: Biological Psychiatry, Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/a88d0f62043cd63ac768026530d6f51ec3f312b6

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In Biological Psychiatry

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In Immunology

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In Oncology

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Citations in the corpus

• Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade (2016, neutral): “Here, tumor cells respond to IFNG as part of a negative feedback event to inhibit the immune response (Spranger et al., 2013; Taube et al., 2012).”
• Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020, result): “This model is consistent with shared recruitment chemokines between CD8 T cells and Tregs (Figure 4F) as well as CD8 T cell requirement for Treg-mediated suppression (Spranger et al., 2013).”
• Molecular and genetic properties of tumors associated with local immune cytolytic activity (2015, neutral): “…for CYT correlations with any transcript (filtering out CTL and NK genes), we found that CYT was best correlated with immunosuppressive factors (Spranger et al., 2013), such as PDL2 (PDCD1LG2), IDO1/2, DOK3 (Lemay et al., 2000), GMCSF receptor (CSF2RA, CSF2RB), and the C1Q complex (Figure 1B).”
• Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. (2016, neutral): “It is interesting to note that PD-L1, IDO, and Treg cell immunoregulation operating within tumors might in fact follow, rather than precede, T cell infiltration (Spranger et al., 2013).”
• Regulation of PD-L1: a novel role of pro-survival signalling in cancer. (2016, background): “Regardless, there is increasing evidence showing that the expression of PD-L1 in cancer cells is mediated by oncogenic activation of signalling pathways and is also regulated by factors in the tumour microenvironment[40].”
• Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab (2017, background): “Most patients with PD had minimal immune response on-therapy, and differential gene analysis did not identify a dominant or single method of tumor-intrinsic immune evasion, suggesting an immune ignorance or immune exclusion mechanism rather than an adaptive resistance mechanism (Salerno et al., 2016”