High macrophage PD-L1 expression not responsible for T cell suppression

Goldman, Naomi; Lomakova, Yelizavet D.; Londregan, Jennifer; Bucknum, Amanda; DePierri, Kelley; Somerville, John; Riggs, James E.

doi:10.1016/j.cellimm.2017.12.013

Cited by 5 publications

(5 citation statements)

References 41 publications

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“…This finding sets PD-L1-dependent allograft tolerance apart from some models of tumor-related immunosuppression, where direct signaling through PD-1 leads to downregulation of the T cell responses (41). However, our data support other models where PD-L1 expression correlates with, but does not directly contribute to, the downregulation of T cell function through PD-1 engagement (42). Thus, our data extend the notion that the role of PD-L1 in immune suppression must be APC and context dependent.…”

Section: Discussionsupporting

confidence: 54%

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

et al. 2019

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It has been demonstrated by us as well as others that eosinophils may alter their phenotype and function based on the local environment (7, 9, 10). Since costimulation plays a critical role in T cell cytokine production and environmental polarization (11, 12), we examined the possibility that eosinophils may lose their tolerogenic properties in the absence of CSB immunosuppression. Cytokine expression was examined in BALB/c (H2 d) lung allografts transplanted into fully MHC-mismatched C57BL/6 (B6) (H2 b) recipient mice. In the absence of immunosuppression, lung allografts had higher levels of Th1-polarizing cytokines IFN-γ and TNF-α than did CSB-treated accepting lung grafts (Figure 1A). Limited amounts of Th2-polarizing cytokines IL-4, IL-13, IL-33, and GM-CSF were evident in lung allografts treated with or without CSB immunosuppression (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.128241DS1). We next evaluated lung-resident eosinophils from both CSB-treated and nonimmunosuppressed grafts. Based on a previously identified eosinophil polarization phenotype (7), we noted higher levels of Th1-defining (or E1-defining) features, such as CXCL9, CXCL10, CXCL11, and iNOS in eosinophils isolated from rejecting compared with CSB-treated lung allografts (Figure 1A). In no group was Th2 (or E2) polarization of eosinophils detected (Supplemental Figure 1A). Flow cytometric characterization demonstrated an absence of MHC II and costimulatory molecules such as CD80, CD86, and CD40. However, there were high levels of recipient-derived MHC I (H2K b), PD-L1, and CD101 on lung-resident eosinophils in the absence of CSB (Figure 1B). Notably, we did not detect BALB/c-derived H2 d-MHC on graft-resident eosinophils, indicating a lack of "cross-dressing" or antigen swapping for donor derived-antigens (ref. 13 and Supplemental Figure 1B). Thus, while eosinophils from rejecting lungs resembled those from accepting lungs in some aspects, we did observe some differences. It is thus possible that in the absence of immunosuppression, eosinophils may contribute to graft rejection rather than acceptance, specifically because CD101 expression has been previously associated with an inflammatory eosinophil subtype (14). In order to evaluate this directly, we conditionally depleted eosinophils from B6 iPHIL mice, in which the diphtheria toxin (DT) receptor is expressed under the control of the eosinophil peroxidase promoter (Supplemental Figure 1C and ref. 15). DT-treated mice or saline-injected controls were challenged with a BALB/c lung allograft in the absence of immunosuppression. Surprisingly, mice depleted of eosinophils had higher grades of rejection (Figure 1C), increased numbers of lung-resident T lymphocytes, increased rates of T cell proliferation, and increased effector cell differentiation by day 4 after engraftment (Figure 1D). These patterns of T lymphocyte activation and infiltration were especially prominent for CD8 + T cells. CD4 + T cell proliferation did ...

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Section: Discussionsupporting

confidence: 54%

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

et al. 2019

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“…These results were corroborated by our expression analysis of immune markers using RNA sequencing (RNA-seq) data ( Figure 6D ), which found PDCD1 (PD-1) expression, a co-inhibitory checkpoint protein expressed by activated CD8 + T cells ( Simon and Labarriere, 2018 ), to be higher (p < 0.05) in later-onset HNSC, which also showed suggestively elevated CD8 + T cells ( Figure 6B ). Our immune marker analysis also found CD274 (PD-L1) expression, strongly associated with tumor macrophages ( Goldman et al, 2018 ), to be elevated in later-onset SARC ( Figure 6D ). For young adult cases, several immune checkpoint genes showed trends of elevated (albeit not significant) expression in KIRP (which had significantly higher dendritic cell fractions), suggesting these tumors may be suitable for treatments using immune checkpoint inhibitors.…”

Section: Resultsmentioning

confidence: 55%

Genomic and molecular features distinguish young adult cancer from later-onset cancer

et al. 2021

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“…A subset demonstrate occasional programmed cell death ligand 1-positive tumor-associated macrophages, however the therapeutic implications of programmed cell death ligand 1-positive macrophages remains unclear. Some literature suggests that they may play an immunosuppressive role and therefore imply potential benefit from anti-programmed cell death 1/programmed cell death ligand 1 immunotherapy,28 but other work has shown no association with T cell suppression 29…”

Section: Discussionmentioning

confidence: 99%

Emerging biomarkers in ovarian granulosa cell tumors

Mills

Chinn

Rauh

et al. 2019

Int J Gynecol Cancer

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ObjectiveAlthough the majority of ovarian granulosa cell tumors can be successfully managed with surgery, a subset require chemotherapy for residual and recurrent disease. The benefit of chemotherapy in this population, however, remains controversial. There is therefore interest in the development of more tolerable and effective treatment options for advanced ovarian granulosa cell tumors. We report the use of immunohistochemistry to investigate how biomarkers could inform clinical trials in granulosa cell tumors with an emphasis on emerging androgen antagonistic, immunotherapeutic, and anti-angiogenic approaches.MethodsImmunohistochemistry for androgen receptor, the immune markers programmed cell death ligand 1, indoleamine-2,3 dioxygenase, and cluster of differentiation 8, and the vascular marker cluster of differentiation 31 were evaluated on formalin-fixed paraffin-embedded whole tissue sections from 29 cases of adult-type granulosa cell tumors. Results were evaluated with clinicopathologic variables including recurrence.Results59% of granulosa cell tumors were androgen receptor-positive, suggesting a potential role for anti-androgen therapy in this tumor type. In contrast, the targetable immune modulatory molecules programmed cell death ligand 1 and indoleamine-2,3 dioxygenase were scarcely expressed, with no cases showing tumorous programmed cell death ligand 1 and a single case demonstrating very focal tumorous indoleamine-2,3 dioxygenase staining. A minority of cases expressed programmed cell death ligand 1 in occasional tumor-associated macrophages and indoleamine-2,3 dioxygenase in peritumoral vessels. Tumor-infiltrating cytotoxic T cells were also scarce in granulosa cell tumors, arguing against a significant role for immunotherapy in the absence of additional immunostimulation. Cluster of differentiation 31 immunostaining revealed a range of vascular densities across granulosa cell tumors, and future studies evaluating the role of vascular density as a predictor of response to angiogenesis inhibition are warranted. None of the biomarkers investigated were significantly correlated with recurrence, and the only clinicopathologic feature significantly correlated with outcome was stage at presentation.ConclusionsBiomarker data suggest that many ovarian granulosa cell tumors could be candidates for anti-androgen therapy, while the potential role for immunotherapy appears more limited. Vascular density could be useful for identifying optimal candidates for angiogenesis inhibition. Incorporation of these biomarkers into clinical trials could help optimize patient selection.

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High macrophage PD-L1 expression not responsible for T cell suppression

Cited by 5 publications

References 41 publications

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

Eosinophils downregulate lung alloimmunity by decreasing TCR signal transduction

Genomic and molecular features distinguish young adult cancer from later-onset cancer

Emerging biomarkers in ovarian granulosa cell tumors

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