PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

Francisco, Loise; Salinas, Víctor; Brown, Keturah; Vanguri, Vijay K.; Freeman, Gordon J.; Kuchroo, Vijay K.; Sharpe, Arlene H.

doi:10.1084/jem.20090847

Cited by 1,787 publications

(1,632 citation statements)

References 75 publications

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“…51 PD-1 is also highly expressed on T regulatory cells and can promote their proliferation, further downregulating the immune response. 52 We provide evidence that in addition to proteinligand interactions as a mechanism of immune escape, immunomodulatory metabolic pathways are upregulated in medullary carcinoma. IDO-1 is an intracellular enzyme that degrades tryptophan (Trp) to kynurenine.…”

Section: Discussionmentioning

confidence: 85%

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Friedman

Brodsky

et al. 2016

Modern Pathology

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Medullary carcinoma of the colon is a unique histologic subtype of microsatellite unstable colorectal carcinoma but little is known regarding its tumor-immunoregulatory microenvironment. The aims of this study were to characterize the immune environment of medullary carcinoma and compare it with other microsatellite unstable and microsatellite stable colorectal carcinomas. An initial gene expression microarray analysis of six cases of medullary carcinoma was used to detect potentially differentially expressed genes. We extended this analysis utilizing genomic data from the Cancer Genome Atlas to compare eight cases of medullary carcinoma with other microsatellite unstable and stable carcinomas. Finally, we evaluated expression of key immune pathway proteins and lymphocyte subsets via immunohistochemistry of a large group of medullary carcinomas (n = 105) and compared these findings with three other groups: poorly differentiated, microsatellite unstable well-differentiated and microsatellite stable well-differentiated carcinomas. Microarray and the Cancer Genome Atlas data analysis identified significant upregulation of several immunoregulatory genes induced by IFNγ including IDO-1, WARS (tRNA(trp)), GBP1, GBP4, GBP5, PDCD1 (PD-1), and CD274 (PD-L1) in medullary carcinoma compared with other microsatellite unstable and microsatellite stable tumors. By immunohistochemistry, IDO-1 was expressed in 64% of medullary carcinomas compared with 19% (9/47) of poorly differentiated carcinomas, 14% (3/22) of microsatellite unstable, and 7% (2/30) of the microsatellite stable well-differentiated carcinomas (Po 0.0001). tRNA(trp) was overexpressed in 81% (84/104) of medullary carcinomas, 19% (9/47) of poorly differentiated, 32% (7/22) of microsatellite unstable, and 3% (1/30) of microsatellite stable well-differentiated carcinomas (Po 0.0001). Medullary carcinoma had higher mean CD8+ and PD-L1+ tumor-infiltrating lymphocytes compared with all other groups (P o0.0001). This study demonstrates overexpression of several immunoregulatory genes in microsatellite unstable colorectal carcinomas and that expression of these genes and proteins is more prevalent in the medullary carcinoma subtype, which may be of use both diagnostically and therapeutically.

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Section: Discussionmentioning

confidence: 85%

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Friedman

Brodsky

et al. 2016

Modern Pathology

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“…Hence, viral factor(s) may increase CD4 + CD25 high Foxp3 + T cell numbers in BLV‐infected cattle, although BLV infects B cells whereas HIV and HTLV‐I infect T cells. In a previous study, PD‐L1 was associated with stable expression of Foxp3 in CD4 + CD25 + Foxp3 + T cells, and enhanced Treg function 47. Moreover, PD‐L1 promoted the development of CD4 + CD25 + Foxp3 + T cells from naïve CD4 + T cells in the presence of TGF‐β 47.…”

Section: Discussionmentioning

confidence: 93%

Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

Ohira

Nakahara

Konnai

et al. 2016

Immunity, Inflammation and Disease

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CD4+CD25highFoxp3+ T cells suppress excess immune responses that lead to autoimmune and/or inflammatory diseases, and maintain host immune homeostasis. However, CD4+CD25highFoxp3+ T cells reportedly contribute to disease progression by over suppressing immune responses in some chronic infections. In this study, kinetic and functional analyses of CD4+CD25highFoxp3+ T cells were performed in cattle with bovine leukemia virus (BLV) infections, which have reported immunosuppressive characteristics. In initial experiments, production of the Th1 cytokines IFN‐γ and TNF‐α was reduced in BLV‐infected cattle compared with uninfected cattle, and numbers of IFN‐γ or TNF‐α producing CD4+ T cells decreased with disease progression. In contrast, IFN‐γ production by NK cells was inversely correlated with BLV proviral loads in infected cattle. Additionally, during persistent lymphocytosis disease stages, NK cytotoxicity was depressed as indicated by low expression of the cytolytic protein perforin. Concomitantly, total CD4+CD25highFoxp3+ T cell numbers and percentages of TGF‐β+ cells were increased, suggesting that TGF‐β plays a role in the functional declines of CD4+ T cells and NK cells. In further experiments, recombinant bovine TGF‐β suppressed IFN‐γ and TNF‐α production by CD4+ T cells and NK cytotoxicity in cultured cells. These data suggest that TGF‐β from CD4+CD25highFoxp3+ T cells is immunosuppressive and contributes to disease progression and the development of opportunistic infections during BLV infection.

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“…26,29 Since PM21-NK cells produce IFNγ in response to SKOV-3 cells, PM21-NK cells should also have a similar effect on tumors to upregulate PD-L1 expression on their surface.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, Tregs developed from a miniscule subpopulation of donor T cells (<0.1% of total human lymphocytes) transferred with PM21-NK cells. Prior studies have shown that PD-L1 is critically required for the induction of Tregs from naïve CD4 T cells as well as their maintenance and immunosuppressive function 29 and the induction of its expression was thought to be caused mostly by CD8 T cells. 26 PD-L1 can also increase Treg content in PM21-NK cell product and decrease the NK/T cell ratio in vitro (Supplemental Figure 6).…”

Section: Discussionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

Cited by 1,787 publications

References 75 publications

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Medullary carcinoma of the colon: a distinct morphology reveals a distinctive immunoregulatory microenvironment

Bovine leukemia virus reduces anti‐viral cytokine activities and NK cytotoxicity by inducing TGF‐β secretion from regulatory T cells

PD-L1 blockade enhances anti-tumor efficacy of NK cells

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