Combination rhIL-15 and Anti-PD-L1 (Avelumab) Enhances HIVGag-Specific CD8 T-Cell Function

Bruktawit A Goshu; Hui Chen; Maha Moussa; Jie Cheng; Marta Catalfamo

doi:10.1093/infdis/jiaa269

. 2020 May 20;222(9):1540–1549. doi: 10.1093/infdis/jiaa269

Combination rhIL-15 and Anti-PD-L1 (Avelumab) Enhances HIVGag-Specific CD8 T-Cell Function

Bruktawit A Goshu ^1,², Hui Chen ^1,², Maha Moussa ¹, Jie Cheng ¹, Marta Catalfamo ^1,^✉

PMCID: PMC7529035 PMID: 32433762

Abstract

In chronic HIV infection, virus-specific cytotoxic CD8 T cells showed expression of checkpoint receptors and impaired function. Therefore, restoration of CD8 T-cell function is critical in cure strategies. Here, we show that in vitro blockade of programmed cell death ligand 1 (PD-L1) by an anti-PD-L1 antibody (avelumab) in combination with recombinant human interleukin-15 (rhIL-15) synergistically enhanced cytokine secretion by proliferating HIVGag-specific CD8 T cells. In addition, these CD8 T cells have a CXCR3⁺PD1^−/low phenotype, suggesting a potential to traffic into peripheral tissues. In vitro, proliferating CD8 T cells express PD-L1 suggesting that anti-PD-L1 treatment also targets virus-specific CD8 T cells. Together, these data indicate that rhIL-15/avelumab combination therapy could be a useful strategy to enhance CD8 T-cell function in cure strategies.

Keywords: HIV-specific CD8 T cells, rhIL-15, PD-L1 blockade

In vitro PD-L1 (avelumab) in combination with rhIL-15 synergistically enhanced cytokine secretion by proliferating HIVGag-specific CD8 T cells with a CXCR3⁺PD1^−/low phenotype. In addition, avelumab targeted PD-L1⁺ proliferating HIVGag-specific CD8 T cells.

Persistent immune activation remains the hallmark of chronic HIV infection despite successfully suppressed viral replication by combination antiretroviral therapy (cART) [1, 2]. During viral infections, CD8 T cells are critical players in controlling viral replication. In the context of human immunodeficiency virus (HIV) infection, these cells possess impaired effector function and are characterized by an activated/exhausted phenotype with higher expression of several checkpoint receptors [3–10]. Among them, the programmed cell death protein 1/programmed cell death ligand 1 (PD1/PD-L1) pathway has been intensively investigated because of its critical role in regulating the function of virus-specific CD8 T cells [10, 11].

PD1 is expressed on T cells, B cells, natural killer (NK) cells, and myeloid cells. In T cells, PD1 expression is induced upon T-cell receptor (TCR) stimulation and is downregulated when pathogen is cleared [11–14]. PD1 binds to 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed in various cells from lymphoid and nonlymphoid tissues. In contrast, the expression of PD-L2 is more restricted to antigen-presenting cells, including dendritic cells and B cells, and its expression is inducible in macrophages [11, 15, 16].

In the context of chronic HIV infection, the PD1/PD-L1 pathway has been shown to contribute to the pathogenesis of the infection [4, 8, 17, 18]. In particular, HIV-specific CD8 T cells showed reduced effector function, including proliferation, cytokine secretion, and cytotoxic activity, and are more susceptible to undergo apoptosis [4, 9]. In addition, recent evidence has shown that expression of checkpoint receptors, including PD1, by HIV-infected cells contributes to viral persistence, and blockade of PD1 promotes latency reversal [19–22]. Therefore, the PD1/PD-L1 pathway has been highlighted as a therapeutic intervention to restore immune function and to target the viral reservoir [10, 23].

A phase 1 clinical trial in patients with HIV infection was performed using an anti-PD-L1 antibody (BMS-936559). This study showed that treatment led to increased cytokine secretion by HIV-specific CD8 T cells while no changes were observed in the viral reservoir [24]. This study suggests that combination therapies improving immunity against HIV and targeting the viral reservoir may be more efficacious.

Studies in simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs) have shown that blockade of the PD1/PD-L1 pathway with an anti-PD1 monoclonal antibody (mAb) enhanced cellular and humoral immunity against SIV [25–29]. In a recent preclinical study, we tested the effects of an anti-PD-L1 antibody (avelumab) in combination with recombinant human interleukin-15 (rhIL-15). IL-15, a common γ-chain cytokine, was included in the combined therapy because of its well-known biological effects on the homeostasis and function of CD8 T and NK cells [30–35]. Administration of anti-PD-L1 (avelumab) and rhIL-15 in SIV-infected RMs led to expansion of SIV-specific CD8 T cells that showed the capacity to degranulate, produce cytokines, and had the potential to traffic to peripheral tissue. However, no effect was observed in viral control after discontinuation of cART [36].

In the present study, we evaluate the in vitro effect of combination rhIL-15/avelumab on HIVGag-specific CD8 T cells. We found that rhIL-15/avelumab enhanced proliferation and cytokine secretion of HIVGag-specific CD8 T cells that were CXCR3⁺PD1^−/low. In addition, we show that in vitro proliferating virus-specific CD8 T cells expressed PD-L1 and therefore can be targeted by avelumab, an unrecognized effect of this treatment in antigen-specific CD8 T cells. These data suggest that this combination treatment may be a useful tool to expand virus-specific CD8 T cells with functional capacity in cure strategies. In addition, this combination may be an efficacious strategy for the in vitro expansion of antigen-specific CD8 T cells in the setting of personalized medicine.

METHODS

Proliferation and Cytokine Secretion Assay

Peripheral blood mononuclear cells (PBMCs) were thawed with X-Vivo media (Lonza) containing Benzonase nuclease (Millipore Sigma). After 2 hours of resting, cells were labeled with Cell Trace Violet (CTV; Thermo Fisher Scientific/Invitrogen) and plated in the presence of either HIVGag peptide pool (2 μg/mL; National Institutes of Health [NIH] AIDS reagent program) or cytomegalovirus, Epstein-Barr virus, and influenza virus (CEF) peptide pools (5 μg/mL; NIH AIDS reagent program) and dimethyl sulfoxide (DMSO) as control. These conditions were cultured in the presence or absence of a fully human anti-PD-L1 mAb (MSB0010718C, avelumab; EMD-Serono) and rhIL-15 (National Cancer Institute-Frederick, Frederick, MD). rhIL-15 was produced under current good manufacturing practice conditions in an Escherichia coli system as previously described [37]. Avelumab was titrated in the presence or absence of rhIL-15 (100 ng/mL) using PBMCs from apheresis of healthy volunteers at concentrations from 0 to 0.002, 0.02, 0.2, 2, and 20 μg/mL.

After 5 days of culture, cells were restimulated with HIVGag peptide or CEF peptide pools as previously described [38]. In brief, cells were incubated with the peptide pools or DMSO as control. After 2 hours of stimulation, brefeldin A (Calbiochem) was added and cells were cultured for an additional 4 hours. Cells were harvested and stained with LIVE/DEAD staining (Invitrogen). Prior to staining, cells were incubated with 1 μg/mL human IgG (Sigma) to block Fc receptors followed by staining with a cocktail of mAbs for the following surface markers: CD3 (clone SP34.2), CD4 (clone L200), PD1 (clone EH12.1), PD-L1 (MIH1), and CD183 (clone 1C6/CXCR3) (all BD Biosciences) and CD8 (clone 3B5; Thermo Fisher Scientific). After surface staining, cells were fixed and permeabilized with Cytofix/Cytoperm (BD Biosciences), followed by staining with mAbs against interferon-γ (IFN-γ; clone B27), tumor necrosis factor-α (TNF-α; clone MAb11), and IL-2 (MQ1-17H12) (all BD Biosciences). Cells were acquired in a BD FACS Symphony flow cytometer and analyzed using FlowJo.

Analysis was performed by flow cytometry using FlowJo 10. High dimensional flow cytometry analysis was performed using FlowSOM (Flow Self Organizing Map, FlowJo) [39]. FlowSOM is an algorithm that builds a self-organizing map and computes a meta-clustering result. In this analysis manual gates were applied to exclude dead cells and doublets to gate on CD8 T cells (CD3⁺CD8⁺). Live CD8 T cells (2000 from each HIV-infected patient) were concatenated for each culture condition: DMSO, and HIVGag peptides in the presence or absence of rhIL-15 and avelumab. Clustering was performed based on 6 selected surface and intracellular markers: CXCR3, PD1, IL-2, IFN-γ, TNF-α, and CTV.

Statistical Analysis

Statistical analysis was performed using a nonparametric paired Wilcoxon test for comparing between culture conditions. P value < .05 was considered significant.

RESULTS

Avelumab Blocks PD-L1 in Proliferating Antigen-Specific CD8 T Cells

We first determined the effect of rhIL-15 and anti-PD-L1 (avelumab) on the proliferation of human virus-specific CD8 T cells from healthy controls (n = 8). PBMCs from apheresis of healthy volunteers were stimulated with CEF peptide pools and increasing concentrations of avelumab (0–20 μg/mL) in the presence or absence of 100 ng/mL rhIL-15 (Figure 1) [40, 41].

Avelumab alone had little effect on the proliferation of CEF-specific CD8 T cells (Figure 1B). In contrast, rhIL-15 increased the proliferation of CD8 T cells in an antigen independent manner (DMSO control) and enhanced the proliferation of CEF-specific CD8 T cells (Figure 1B).

In addition, we found that in vitro, proliferating (CTV^low) CEF-specific CD8 T cells expressed PD-L1 (median 46.60%; interquartile range [IQR], 25.50%–56.63%) and its expression was increased when rhIL-15 was present in the culture (median 52.95%; IQR, 39.62%–80.01%; Figure 1A and 1C). This effect was also observed in the nonproliferating CTV^high CD8 T cells, although to a lesser degree (Figure 1C middle panel). Avelumab efficiently blocked the staining of PD-L1 in proliferating CTV^lowCEF-specific CD8 T cells (Figure 1A and 1C).

These data show that avelumab, in addition to targeting PD-L1 expressed on antigen presenting cells and other myeloid cells, can also target PD-L1 expressed by antigen-specific CD8 T cells and, in combination with rhIL-15, enhances proliferation.

Combination rhIL-15/Avelumab Promotes Cytokine Secretion by Proliferating Virus-Specific CD8 T Cells From Healthy Volunteers and HIV-Infected Patients

Next, we determined the impact of rhIL-15/avelumab on T-cell function in PBMCs from healthy controls (n = 6) and HIV-infected patients (n = 10). We anticipated that in the context of HIV infection, immune activation will drive higher expression of checkpoint receptors. To assure complete in vitro blockade of PD-L1 we used a higher concentration of avelumab (20 μg/mL) similar to that previously described [42].

As shown above, avelumab alone at this concentration did not elicit a strong effect on the proliferation of CD8 T cells. Because of the limited number of PBMCs from patients and healthy volunteers, in the next set of experiments we used as controls DMSO and DMSO in the presence of rhIL-15 because of its antigen-independent effects on CD8 T cells. We stimulated PBMCs from healthy controls and HIV-infected patients with CEF or HIVGag peptide pools, respectively. At day 5 of culture, cells were restimulated with the peptide pools and analyzed for the capacity to secrete cytokines by proliferating virus-specific CD8 T cells [38].

We found that in healthy controls (Figure 2) the use of a single treatment (either avelumab or rhIL-15) did not have an effect on the cytokine secretion IFN-γ (Figure 2B), TNF-α (Figure 2C), and IL-2 (Figure 2D) by CTV^lowCEF-specific CD8 T cells when compared with CEF stimulation alone (Figure 2). In contrast, combination rhIL-15/avelumab significantly increased the secretion of IFN-γ (P = .031; Figure 2B) and TNF- α (P = .031; Figure 2C) but not IL-2 (P = .063; Figure 2D) by proliferating CTV^lowCD8 T cells.

Next, we assessed if similar effects can be modulated in HIVGag-specific CD8 T cells in which HIV-driven immune activation promotes activation/exhaustion leading to poor effector function. PBMCs from HIV-infected patients (n = 10; Table 1) with median CD4 T-cell counts 607 cells/μL (IQR, 353–829 cells/μL) and suppressed viremia (median, < 50 copies/mL; IQR, < 20–114 copies/mL) were cultured as described above.

Table 1.

CD4 and CD8 T-Cell Counts, and Viral Load of HIV-Infected Patients

	CD4, cells/μL	CD8a, cells/μL	CD4/CD8 Ratioa	HIV (bDNA or RNA), copies/mL
Median (IQR)	607 (353–829)	749 (480–1089)	0.72 (0.54–0.89)	<50 (< 20–114)

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Abbreviations: bDNA, branched DNA; IQR, interquartile range.

aCD8 count was not available for 2 out of the 10 patients.

rhIL-15 alone significantly increased IFN-γ (P = .027; Figure 2B) and TNF-α (P = .004; Figure 2C) secretion by proliferating CTV^low HIVGag-specific CD8 T cells when compared to HIVGag stimulation alone (Figure 2). Similar to that observed in healthy volunteers, avelumab alone had no effect on cytokine secretion by CTV^low CD8 T cells (Figure 2D).

Combination rhIL-15/avelumab enhanced the secretion of cytokines IFN-γ (P = .002; Figure 2B) and TNF-α (P = .002; Figure 2C) but not IL-2 (Figure 2D) by proliferating HIVGag-specific CD8 T cells when compared to HIVGag peptide alone (Figure 2). Together, these data suggest that compared to the single treatment, the combination rhIL-15/avelumab had a synergistic effect on enhancing the functional capacity of HIVGag specific-CD8 T cells.

We recently made the observation that administration of rhIL-15/avelumab in nonhuman primates expanded a proportion of virus-specific CD8 T cells with functional capacity and potential to traffic into peripheral tissues measured by expression of CXCR3 [36].

To determine if similar effects were also observed in PBMCs from HIV-infected patients we analyzed the phenotype of the HIVGag-specific CD8 T cells (Figure 3). We observed that rhIL-15/avelumab enhances IFN-γ secretion (Figure 3B) and TNF-α secretion (Figure 3C) by HIVGag-specific CD8 T cells that were CXCR3⁺PD1⁻ and CXCR3⁺PD1⁺ (expressing PD1^low) phenotype (Figure 3). In contrast, IL-2–secreting cells (Figure 3D) were mostly associated with a CXCR3⁺PD1⁻ CD8 T-cell phenotype (Figure 3).

Figure 3. — Combination rhIL-15 and anti-PD-L1 (avelumab) enhances cytokine secretion by CTV^lowCXCR3⁺PD1^−/low HIVGag-specific CD8 T cells. PBMCs from HIV-infected patients (n = 10) were cultured with HIVGag peptide pool or DMSO (unstimulated control) in the presence or absence of rhIL-15 (100 ng/mL) or avelumab (20 μg/mL) or combination of both. At day 5 of culture, cells were restimulated with DMSO or HIVGag peptides and analyzed by flow cytometry. A, Representative dot plots of the CXCR3⁺PD1⁻, CXCR3⁺PD1⁺, and CXCR3⁻PD1⁺ proliferating (CTV^low) CD8 T cells secreting IFN-γ. B, Frequency of CTV^lowIFN-γsecreting CXCR3⁺PD1⁻, CXCR3⁺PD1⁺, and CXCR3⁻PD1⁺ CD8 T-cell phenotype. C, Frequency of CTV^lowTNF-α secreting, CXCR3⁺PD1⁻, CXCR3⁺PD1⁺, and CXCR3⁻PD1⁺ CD8 T-cell phenotype. D, Frequency of CTV^lowIL-2 secreting CXCR3⁺PD1⁻, CXCR3⁺PD1⁺, and CXCR3⁻PD1⁺ CD8 T-cell phenotype. Bars represent median and interquartile range. Comparisons between culture conditions were performed by a paired nonparametric Wilcoxon test. P value < .05 was considered significant. Abbreviations: anti-PD-L1, anti-programmed cell death ligand 1; CTV, Cell Trace Violet; DMSO, dimethyl sulfoxide; HIV, human immunodeficiency virus; IFN-γ, interferon-γ; IL, interleukin; PBMC, peripheral blood mononuclear cells; rhIL-15, recombinant human interleukin-15; TNF-α, tumor necrosis factor-α.

To better characterize the HIVGag-specific CD8 T cells induced by rhIL-15/avelumab, we performed multidimensional single-cell analysis using the FlowSOM algorithm as described [36, 39]. FlowSOM enables the automated distribution and visualization of highly similar cells into distinct clusters by their expression of selected parameters including CXCR3, PD1, IL-2, IFN-γ, TNF-α, and CTV (Figure 4). Eight clusters, indicated by colors and numbers, were identified. Each cluster contains nodes representing heterogenous cell populations inside the clusters (Figure 4). The circle inside the nodes indicates the abundance of the population. The relative expression (fluorescence intensity) of the parameters are represented by the pie chart inside each node and the height of each wedge within the chart is proportional to the expression of the marker (Figure 4); an amplified visualization of the clusters is shown in Supplementary Figure 1.

Across the conditions, most of the nonproliferating (CTV^high, red wedge) and/or limited CTV dilution were located in clusters (Cl)-1, Cl-5, Cl-6, and Cl-7 (Figure 4 and Supplementary Figure 1). The highest proportion of nonproliferating cells was contained in Cl-7 (Supplementary Figure 2). The high proliferating cells, CTV^low CD8 T cells, were mainly localized in Cl-3, Cl-4, and a very discreet Cl-2 (Figure 4 and Supplementary Figure 2).

Discreet changes in these clusters were observed in the HIVGag and HIVGag in the presence of avelumab culture conditions (Figure 4 and Supplementary Figure 2). In contrast, stimulation in the presence of rhIL-15 and avelumab led to proliferating CTV^low CD8 T cells in Cl-3 and Cl-4 that were CXCR3⁺PD1^−/low, and had the ability to secrete IFN-γ, TNF-α, and IL-2 (Figure 4, Supplementary Figure 1, and Supplementary Figure 2).

These data show that in vitro rhIL-15/avelumab promotes expansion of HIV-specific CD8 T cells with enhanced functional properties and the potential to traffic into tissues.

DISCUSSION

In this study we investigated the effects of rhIL-15/anti-PD-L1 (avelumab) in HIV-specific CD8 T cells. We found that the combination rhIL-15/avelumab synergistically enhanced the effector function of proliferating HIVGag-specific CD8 T cells that express CXCR3⁺PD1^−/low (with the potential to traffic into peripheral tissues). In addition, we found that avelumab can target PD-L1 expressed by proliferating virus-specific CD8 T cells, an unappreciated effect of this therapy.

The effects of PD-L1 blockade on antigen presenting cells, myeloid suppressor cells, and tumor cells have been widely studied [11, 43]. Here, this pathway is likely to contribute during the in vitro activation of HIV-specific CD8 T cells thereby enhancing their functional capacity.

The role of PD-L1 expression by T cells, and specifically by virus-specific CD8 T cells, is yet to be defined. Previously, it has been shown that PD-L1 signaling in CD4 T cells leads to proliferation and secretion of IL-10, promoting cell death [44]. In CD8 T cells, expression of PD-L1 was essential for the survival of effector cells during the contraction phase in an ovalbumin and poly (I:C) immunization mouse model [45]. PD-L1 is involved in virus-specific CD8 T-cell expansion and function as revealed by experiments with the PD-L1 knockout mice in the Friend retroviral mouse infection model [46]. In a murine model of graft-versus-host disease, PD-L1–deficient allogeneic donor CD8 T cells showed reduced secretion of inflammatory cytokines and increased apoptosis [47]. One of the proposed mechanisms is that PD-L1 can interact with CD80 expressed by CD8 T cells and promote survival and expansion of CD8 T cells [48].

In addition, the high cytokine production by PD-L1–deficient CD8 T cells may suggest a role for PD-L1 in tolerance [49]. This hypothesis is supported by a recent report that PD-L1 expression in tumor-infiltrating CD8 T cells promotes tolerance by several mechanisms, including induction of anergy and a T cell-T cell engagement of PD-L1-PD-1. Therefore, PD-L1–expressing T cells can restrain PD1-expressing effector T cells [50].

In humans, expression of PD-L1 by CD8 T cells has been observed in patients with melanoma and its expression is associated with poor outcomes ([51, 52] in Supplementary Material).

The role of PD-L1 expression in T cells during infection is not very well defined. The present data suggest that T cells upon stimulation express PD-L1. While avelumab alone does not have an apparent effect, when combined with rhIL-15 it increases the ability to secrete cytokines by proliferating virus-specific CD8 T cells that have the potential to traffic into peripheral tissues (measured by CXCR3⁺ expression). Similar effects were observed in vivo when this combination was administered in SIV-infected nonhuman primates [36].

rhIL-15 has been used as a single molecule and modifications of the molecule has been designed to create superagonist effects. For instance, in a phase 1 clinical trial the superagonist ALT-803 administered to HIV-infected patients induced HIV transcription and was suggested to be beneficial for viral latency reversal ([53] in Supplementary Material). In SIV-infected RM, the superagonist ALT-803 has also been shown to enhance viral-specific CD8 responses and facilitate their trafficking into B-cell follicles, and transiently reduced viral replication ([54, 55] in Supplementary Material). Recent studies have used an IL-15 superagonist in SIV-infected RMs to study the mechanisms of latency reversal ([56] in Supplementary Material).

IL-15 and other common γ-chain cytokines have been shown to induce PD-L1 expression on T cells [41] ([57] in Supplementary Material). Additionally, IL-15 can promote in vivo expansion of CD8 T cells [37] ([58, 59] in Supplementary Material).

In this current in vitro study in human PBMCs, as well as our most recent in vivo study on RM, when IL-15 is combined with a checkpoint receptor blockade (avelumab), there is synergistically enhanced effector function of HIV/SIV-specific CD8 T cells [36]. Thus, the role of PD-L1 expression in virus-specific CD8 T cells warrants further investigation.

In summary, this in vitro study demonstrates the synergistic effect of rhIL-15 and anti-PD-L1 antibody avelumab on HIVGag-specific CD8 T cells. rhIL-15/avelumab treatment can be a helpful strategy to enhance the function of activated/exhausted HIVGag-specific CD8 T cells. These properties may be explored in cure strategies and other settings in which HIV-specific CD8 T cells need to be expanded in vitro such as in chimeric antigen receptor T-cell therapy.

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

jiaa269_suppl_Supplementary_Figures

Click here for additional data file.^{(6MB, pdf)}

Notes

Acknowledgments. The anti-PD-L1 (MSB0010718C, avelumab) was provided by EMD-Serono, Rockland, MA. The HIVGag and CEF peptide pools were obtained through the National Institutes of Health (NIH)-AIDS Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH. Some mAbs were provided by the NIH-Nonhuman Primate Reagent Resource.

Disclaimer. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Financial support. Leidos Biomedical Research, Inc. has been funded in whole or in part with federal funds from the National Cancer Institute, NIH, under Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Presented in part: American Association of Immunologists Annual Meeting, San Diego, CA, 9–13 May 2019.

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32. Berger C, Berger M, Hackman RC, et al. Safety and immunologic effects of IL-15 administration in nonhuman primates. Blood 2009; 114:2417–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Lugli E, Goldman CK, Perera LP, et al. Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates. Blood 2010; 116:3238–48. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Weng NP, Liu K, Catalfamo M, Li Y, Henkart PA. IL-15 is a growth factor and an activator of CD8 memory T cells. Ann N Y Acad Sci 2002; 975:46–56. [DOI] [PubMed] [Google Scholar]
35. Berard M, Brandt K, Bulfone-Paus S, Tough DF. IL-15 promotes the survival of naive and memory phenotype CD8⁺ T cells. J Immunol 2003; 170:5018–26. [DOI] [PubMed] [Google Scholar]
36. Chen P, Chen H, Moussa M, et al. Recombinant human interleukin-15 and anti-PD-L1 combination therapy expands a CXCR3⁺PD1 ⁻ ^/low CD8 T-cell subset in simian immunodeficiency virus-infected rhesus macaques. J Infect Dis 2020; 221:523–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Waldmann TA, Lugli E, Roederer M, et al. Safety (toxicity), pharmacokinetics, immunogenicity, and impact on elements of the normal immune system of recombinant human IL-15 in rhesus macaques. Blood 2011; 117:4787–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Porichis F, Kwon DS, Zupkosky J, et al. Responsiveness of HIV-specific CD4 T cells to PD-1 blockade. Blood 2011; 118:965–74. [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Van Gassen S, Callebaut B, Van Helden MJ, et al. FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A 2015; 87:636–45. [DOI] [PubMed] [Google Scholar]
40. Perera LP, Goldman CK, Waldmann TA. IL-15 induces the expression of chemokines and their receptors in T lymphocytes. J Immunol 1999; 162:2606–12. [PubMed] [Google Scholar]
41. Kinter AL, Godbout EJ, McNally JP, et al. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 2008; 181:6738–46. [DOI] [PubMed] [Google Scholar]
42. Donahue RN, Lepone LM, Grenga I, et al. Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. J Immunother Cancer 2017; 5:20. [DOI] [PMC free article] [PubMed] [Google Scholar]
43. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26:677–704. [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Dong H, Strome SE, Matteson EL, et al. Costimulating aberrant T cell responses by B7-H1 autoantibodies in rheumatoid arthritis. J Clin Invest 2003; 111:363–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Pulko V, Harris KJ, Liu X, et al. B7-h1 expressed by activated CD8 T cells is essential for their survival. J Immunol 2011; 187:5606–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
46. David P, Megger DA, Kaiser T, et al. The PD-1/PD-L1 pathway affects the expansion and function of cytotoxic CD8⁺ T cells during an acute retroviral infection. Front Immunol 2019; 10:54. [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Saha A, O’Connor RS, Thangavelu G, et al. Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. J Clin Invest 2016; 126:2642–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Ni X, Song Q, Cassady K, et al. PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8⁺ T cells. J Clin Invest 2017; 127:1960–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
49. Latchman YE, Liang SC, Wu Y, et al. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci U S A 2004; 101:10691–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
50. Diskin B, Adam S, Cassini MF, et al. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer. Nat Immunol 2020; 21:442–54. [DOI] [PubMed] [Google Scholar]

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[CIT0048] 48. Ni X, Song Q, Cassady K, et al. PD-L1 interacts with CD80 to regulate graft-versus-leukemia activity of donor CD8⁺ T cells. J Clin Invest 2017; 127:1960–77. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[CIT0050] 50. Diskin B, Adam S, Cassini MF, et al. PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer. Nat Immunol 2020; 21:442–54. [DOI] [PubMed] [Google Scholar]

PERMALINK

Combination rhIL-15 and Anti-PD-L1 (Avelumab) Enhances HIVGag-Specific CD8 T-Cell Function

Bruktawit A Goshu

Hui Chen

Maha Moussa

Jie Cheng

Marta Catalfamo

Abstract

METHODS