The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells
© Lisiero et al.; licensee BioMed Central Ltd. 2014
Received: 26 January 2014
Accepted: 19 March 2014
Published: 15 April 2014
Histone deacetylase (HDAC) inhibitors are a class of agents that have potent antitumor activity with a reported ability to upregulate MHC and costimulatory molecule expression. We hypothesized that epigenetic pharmacological immunomodulation could sensitize tumors to immune mediated cell death with an adoptive T cell therapy.
The pan-HDAC inhibitor, LBH589, was combined with gp100 specific T cell immunotherapy in an in vivo B16 melanoma model and in an in vivo non-tumor bearing model. Tumor regression, tumor specific T cell function and phenotype, and serum cytokine levels were evaluated.
Addition of LBH589 to an adoptive cell transfer therapy significantly decreased tumor burden while sustaining systemic pro-inflammatory levels. Furthermore, LBH589 was able to enhance gp100 specific T cell survival and significantly decrease T regulatory cell populations systemically and intratumorally. Even in the absence of tumor, LBH589 was able to enhance the proliferation, retention, and polyfunctional status of tumor specific T cells, suggesting its effects were T cell specific. In addition, LBH589 induced significantly higher levels of the IL-2 receptor (CD25) and the co-stimulatory molecule OX-40 in T cells.
These results demonstrate that immunomodulation of adoptively transferred T cells by LBH589 provides a novel mechanism to increase in vivo antitumor efficacy of effector CD8 T cells.
KeywordsT cells Tumor immunity Dendritic cells Inflammation
The adoptive transfer of tumor specific T cells is becoming a viable treatment option for many patients with solid tumors. However, despite the ability to specifically target tumors, adoptively transferred cells often fail to survive and persist in vivo. Their ability to retain effector function diminishes quickly and often transforms into a suppressive state, with an inability to mobilize IFN-γ and other critical cellular functions[3–5]. Many strategies have been employed to reverse this balance in favor of an effector T cell response. Strategies such as lymphodepletion prior to adoptive cell transfer and high doses of IL-2 have been shown to significantly increase retention and proliferation of adoptively transferred T cells[6, 7]. In addition, combining these strategies with immunomodulation of the tumor itself has shown the potential to increase responsiveness to immunotherapy.
Histone deacetylase inhibitors (HDACis), such as vorinostat (SAHA) and romidepsin, are approved for the treatment of cutaneous T-cell lymphomas. Such agents act via multiple mechanisms, including cell cycle arrest and activation of the intrinsic death pathway[9, 10]. Acetylation and deacetylation of lysine residues on histone tails and non-histone substrates controls a number of cellular processes including the regulation of transcription, transcription factor stability and cell survival. Histone deacetylases are a class of enzymes responsible for deacetylation of histone proteins and other non-histone protein substrates. Inhibition of histone deacetylases with HDACis, such as vorinostat, can preferentially induce cell cycle arrest, apoptosis, and differentiation in leukemic malignancies and solid tumors. More importantly, HDACis have been shown to enhance tumor immunity by upregulating the expression of major histocompatibility class (MHC) molecules, costimulatory molecules and components involved in tumor necrosis factor (TNF) superfamily signaling[13–17]. However, HDACi’s have also been shown to increase the function of T regulatory cells and increase IDO immunosuppression by dendritic cells[18–20]. These potentially contradictory functions of HDACis in the context of tumor immunity have complicated their inclusion in immunotherapy protocols.
In order to test whether an HDACi could synergize with immunotherapy in an in vivo melanoma model, we utilized LBH589 (Panobinostat) in combination with T cell transfer therapy. LBH589 is a cinnamic hydroxamic acid derivative with broad inhibitory activity of class I, II, and IV HDACs in the low nanomolar range. It has shown clinical efficacy for the treatment of multiple myeloma and Hodgkin’s lymphoma and animal models in doses ranging from 10-100 mg/kg[22, 23]. However, whether LBH589 could similarly enhance adoptive T cell transfer without generating a potentially immunosuppressive milieu had yet to be addressed. We utilized gp100 tumor associated antigen specific Pmel T cell immunotherapy in an in vivo melanoma model in order to address these concerns. Adjuvant administration of LBH589 potently synergized with adoptive cell transfer, and to our surprise, created a highly pro-inflammatory environment that could be measured by significant modulation of serum cytokine levels. This was accompanied by a significant expansion and enhancement of effector function, which occurred in the presence or absence of tumor. Notably, specific release of TNF following restimulation of Pmel T cells and serum cytokine levels of TNF were significantly increased and sustained over time. Taken together with an increase in the T cell specific expression of the TNF superfamily receptor, OX-40, inclusion of LBH589 highlights the potential new role of HDAC inhibitors in modulating and sustaining in vivo T cell function.
LBH589 synergizes with an adoptive cell transfer therapy to reduce tumor burden
LBH589 alters and extends in vivo peripheral cytokine production
Expansion of adoptively transferred cells and reduction of T regulatory cells with LBH589 treatment
Enhanced T cell expansion with LBH589 is not dependent on the presence of tumor
Increased ex vivo polyfunctionality of tumor specific T cells with LBH589
LBH589 enhances markers of activation on tumor specific T cells
Our study addressed whether the adjunctive use of an HDAC inhibitor could synergize with an adoptive cell transfer therapy, without suppressing or compromising a tumor specific effector T cell response. Utilization of LBH589 dramatically enhanced the antitumor activity of an adoptive T cell transfer therapy in a murine B16-F10 subcutaneous melanoma model. Inclusion of LBH589 together with adoptive T cell transfer induced significant regression of established B16 melanoma tumors while generating a systemic proinflammatory cytokine milieu, illustrated by the sustained release of IFN-γ and TNF. Such enhanced antitumor activity was further exemplified by the increased recovery of adoptively transferred Pmel cells, both systemically and intratumorally, together with a drastic reduction in the T regulatory cell population. Surprisingly, enhanced Pmel T cell in vivo expansion and effector function occurred even in the absence of tumor in LBH589 treated groups. Phenotypically, following adoptive transfer and treatment with LBH589, Pmel T cells preferentially expressed high levels of the TNF receptor family member, OX-40, and secreted high levels of TNF following ex vivo restimulation. These results highlight the significant antitumor and immunomodulatory activities of LBH589.
Our findings demonstrated that the adjunctive use of LBH589 with adoptive T cell transfer significantly reduces T regulatory cell populations in the periphery and within the tumor. This is significant when considering the immunomodulatory properties of T reg cells in the context of a tumor mass. Pre-clinical studies have demonstrated that the infiltration of T reg cells specifically within a tumor mass decreases effector T cell proliferation and function. Furthermore, pharmacological blockade of a known T reg cell marker, CTLA-4, restored effector T cell proliferation and synergized with a therapeutic vaccine. In fact, the ability to modulate T regulatory cell populations in vivo and significantly elevate the T effector to T regulatory cell ratio can act as a positive predictive factor for tumor rejection and promotes effector cell proliferation and cytokine secretion. Clinically, high levels of peripheral T regulatory cell populations are negatively associated with therapeutic responsiveness after lymphodepletion and adoptive cell transfer in patients. Although this T regulatory cell population may not be indicative of a tumor educated population, it may highlight the overall status of immune responsiveness. Our results, as well as evidence from both pre-clinical and clinical studies, highlight the significance of T regulatory cell function in the context of immune based therapies. Thus, the selective pharmacological modulation of T effector function and T regulatory cell populations to significantly increase anti-tumor activity makes LBH589 an extremely attractive therapeutic that may abrogate the need for lymphodepletion prior to adoptive cell transfer. Future studies are needed to address this hypothesis.
Our results also indicated an enhanced inflammatory cytokine environment and state of T cell responsiveness. In this light, we tested the ability of LBH589 to modulate T cell function in non-tumor bearing hosts. We determined that the majority of immunological effects seen in our treatment regimen were due to an overwhelming enhancement of T cell proliferation and function by LBH589, even in the absence of tumor. Although one of the limitations of our experimental design was that it did not allow us to specifically distinguish whether LBH589 acts directly on adoptively transferred T cells, dendritic cells, or endogenous lymphocytes we hypothesize that in this lymphopenic environment, the majority of effects are on the activated T cells themselves. This is supported by the fact that the lymphocytes in the spleen of LBH589 treated groups were composed primarily of Pmel CD8+ T cells, and a significantly lower percentage of CD4+ T cells and CD4+ T regulatory cells. The enhancement of T cell function we observed was dominated by a more than 2 fold change in the tumor peptide (gp10025-33) specific secretion of TNF ex vivo, mirroring the data observed in serum cytokine levels. This is the first study that demonstrates a pharmacological enhancement of polyfunctional T cell status by an HDAC inhibitor. The potency of this response was magnified if a third dendritic cell vaccination was utilized at day 14 of this treatment scheme. This resulted in a lethal cytokine storm in a majority of mice treated with immunotherapy and LBH589. From this data we concluded that only one dendritic cell revaccination was necessary to mount an effective anti-tumor response without adverse events. This warrants further investigation into the molecular mechanisms for HDACi mediated regulation of inflammatory cytokines, and whether sub-optimal doses of IL-2 can be utilized to support adoptively transferred cells. These results are also surprising considering previous studies have shown that LBH589 impairs the function and phenotype of dendritic cells by downregulating co-stimulatory molecules and repressing inflammatory cytokine production. Our own studies, which utilize a peptide specific dendritic cell vaccine in combination with adoptive T cell transfer, demonstrated robust tumor specific T cell specific proliferation and cytokine production following dendritic cell revaccination. Future studies will investigate whether LBH589 modulates dendritic cell function in the therapeutic context of adoptive T cell transfers.
HDAC inhibitors have been shown to preferentially regulate the expression of TNF superfamily members, including TNF receptors, and TNF associated ligands in tumors. The class I HDAC inhibitor, depsipeptide increased the expression of TNF-related apoptosis-inducing ligand (TRAIL) on chronic lymphocytic leukemia (CLL) and acute lymphoblastic leukemia cell lines, sensitizing them to death receptor-induced apoptosis. Additionally, inhibition of HDAC11 in Hodgkin lymphoma increases the expression of OX-40 ligand and inhibits the generation of IL-10 producing T regulatory cells in vitro. However, the modulation of TNF family members by HDAC inhibitors in CD8+ T cells has not been previously demonstrated. In this study, we demonstrated an increase in the specific expression of TNF and TNF superfamily member, OX-40, by tumor-specific T cells. TNF has been shown to be crucial for the priming and effector function of CD8 T cells during an antitumor immune response[35, 36]. This is especially significant considering that proper costimulation and cytokine support for effective T cell responses is severely lacking during tumor surveillance. OX-40 is a critical co-stimulatory molecule that is necessary for effector function, survival, and memory generation[35, 37]. In vivo, OX-40 agonistic antibodies potentiate CD8 T cell memory generation and antitumor activity[38–40]. Therefore, inclusion of LBH589 in current adoptive cell transfer protocols could potentially enhance the anti-tumor activity of T cells by providing in vivo co-stimulation through OX-40. Taken together with the increased expression of the high affinity IL-2 receptor, CD25, we believe that increased expression of OX-40 imparts a highly activated phenotype to CD8+ T cells that allows them to compete for proliferative cytokines (IL-2) and co-stimulation through OX-40. We believe that LBH589 may specifically modulate the proliferation, retention, and responsiveness of CD8 T cells.
We have demonstrated that LBH589 potentiates the function of CD8 T cells, and this occurs in the presence and absence of tumor. We demonstrated that an HDAC inhibitor has the potential to sensitize tumor specific cells to peptide specific vaccination and acquisition of full T cell effector function, by increasing peptide specific secretion of TNF, expression of the co-stimulatory receptor, OX-40, and expression of the IL-2 high affinity receptor, CD25. Further investigations need to be conducted in order to determine whether LBH589 directly modulates histone acetylation in CD8+ T cells and transcriptionally regulates T cell effector function and expression of TNF superfamily members. Furthermore, although the HDAC target(s) of LBH589 inhibition responsible for these immunomodulatory activities is unclear, this study provides additional mechanistic insight into the ability of HDACs to specifically regulate T cell function and anti-tumor activity. Our results highlight LBH589 as a safe and effective adjuvant to regulate the proliferation and function of adoptively transferred tumor specific T cells, and potentially warrants its inclusion in future ACT human clinical trials.
The histone deacetylase inhibitor, LBH589, synergizes with adoptive T cell transfer therapy and helps mediate potent antitumor activity in an in vivo melanoma model. In this immunotherapeutic context, LBH589 enhanced the retention of polyfunctional tumor specific T cells, promoted systemic cytokine responses, and increased the effector to regulatory T cell ratio. These results demonstrate the ability of a pan histone deacetylase inhibitor to effectively modulate the antitumor response and warrants further studies for future clinical use.
Animals and cell lines
All mice were bred and kept under defined-flora pathogen-free conditions at the Association for Assessment and Accreditation of Laboratory Animal Care-approved animal facility of the Division of Experimental Radiation Oncology at the University of California Los Angeles. Mice were handled in accordance with the University of California Los Angeles animal care policy and approved animal protocols. The B16-F10 murine melanoma cell line was obtained from American Type Culture Collection (Rockville, MD).
Tumor implantation and lymphodepletion
For studies analyzing tumor growth over time in an in vivo melanoma model, C57BL/6 mice (6-12 weeks of age) were implanted subcutaneously in the lower left flank with 2 × 105 B16-F10 melanoma cells and allowed to establish for 10 days. For studies analyzing tumor infiltrating lymphocytes, 2.5 × 105 B16-F10 melanoma cells were implanted in the same location and allowed to establish for 10 days.
One day prior to adoptive T-cell transfer, lymphopenia was induced by 500 cGy total body irradiation.
Adoptive T cell transfer and dendritic cell vaccination
Pmel-1 T cells and bone marrow derived dendritic cells were generated as previously described. In brief, naïve Pmel-1 splenocytes were activated with human gp10025-33 peptide (NH2-KVPRNQDWL-OH, 1 u g/ml; Biosynthesis, Lewisville, TX) and 100 IU/ml human IL-2 (National Cancer Institute Preclinical Repository, Developmental Therapeutics Program) for 72 hours. These cells were then re-cultured for an additional 48 hours in 100 IU/ml IL-2 without hgp100. Pmel-1 T-cells (5 × 106) were injected i.v. in 0.1 ml PBS.
Bone marrow derived dendritic cells were generated as previously described. Bone marrow cells from the femurs and tibias of 2 Bl/6 mice were initially cultured overnight in a petri dish in RPMI 1640 supplemented with 10% FBS and pencillin/streptomycin. The next day, non-adherent cells were collected and washed twice with media and re-cultured in 50 ml of fresh media containing 2 ng/ml recombinant murine GM-CSF and 10 ng/ml recombinant murine IL-4 (Peprotech). Cells were then plated at 1 ml per well in 24 well plates and cultured for 3 days. On the third day, 0.5 ml of media was removed and 1 ml of new media containing 10 ng/ml IL-4 and 2 ng/ml GM-CSF was added. On the 7th day, cells were harvested by using a syringe plunger to scrape cells from the bottom of each well. Once harvested, dendritic cells were pulsed with human gp10025–33 peptide at a concentration of 10 μM for 90 min at room temperature. Approximately 5 × 105 were injected subcutaneously at four sites on the back. IL-2 (5 × 105 IU) was administered in 500 ul and given as an intraperitoneal injection. LBH589 (a kind gift from Novartis) was given at a dose of 5 mg/kg and administered at the same time as IL-2.
Ex vivo Pmel-1 T cell stimulation and intracellular FACS staining
After the indicated time periods following adoptive T cell transfer, splenocytes were enumerated and restimulated with or without hgp10025-33 peptide. GolgiPlug protein transport inhibitor (BD Biosciences) and allophycocyanin-conjugated anti-CD107a mAb (2 ug, clone 1D4B; BD Biosciences) were added to each well containing T cells. Cells were stimulated at 37°C for 0, 1, 2, or 5 hours. After each time period, cells were placed on ice in the dark until all cells could be stained at the same time. Cells were washed with PBS containing 2% FBS and stained with CD8 mAb, Thy1.1 mAb, and a fluorescent cell viability stain (Live/Dead, Invitrogen) on ice. Cells were fixed and permeabilized with intracellular fixation and permeabilization buffer set from eBioscience. Intracellular staining was then completed by staining with IFN-γ, TNF-α and IL-2 mAbs on ice in the dark.
Flow cytometry and mAbs
Spleens and tumors were harvested from mice after adoptive transfer. Spleens were passed through 70 u m cell strainers and lymphocytes were obtained after hypotonic lysis. Approximately 1 × 106 were used for each staining. To determine the number of tumor-infiltrating lymphocytes (TILs), tumors were weighed and minced with a scalpel. The tumor was then digested in collagenase with DNase for 2 hours on a rotator. Small mononuclear cells within the tumor were enumerated by trypan blue exclusion, with approximately 1 × 106 lymphocytes used for staining. TILs were calculated by determining the absolute number of CD8+ Thy1.1+ cells per milligram of tumor.
Fluorochrome conjugated Abs to CD4 (clone RM4-5), CD8 (clones 5H10 and 53-6.7), CD107a (clone 1D4B), IFN-γ (clone XMG1.2), TNF-α (clone MP6-XT22) and IL-2 (clone JES6-5H4) were obtained from BD Biosciences or Biolegend. Fluorochrome conjugated Abs to Thy1.1 (clone HIS51) and FoxP3 (clone FJK-16 s) were obtained from eBioscience. For intracellular cytokine staining, cells were washed with PBS containing 2% FBS and subsequently stained with surface markers. After extracellular staining, cells were fixed with Fixation Buffer (eBioscience) and permeabilized with Permeabilization Buffer (eBioscience). Intracellular staining was completed in Permeabilization Buffer on ice in the dark. Cells were stored at 4°C until analysis.
All FACS analysis was performed with the use of an LSRII (BD Biosciences). Gates were set based on samples stained with all fluorophores minus one. Only viable cells, as determined by negative staining with a dead cell stain (Live/Dead Fixable Near-IR Dead Cell Stain Kit, Invitrogen), were included in subsequent analyses. Data were analyzed using FlowJo software (Treestar).
Assessment of serum cytokine levels
Serial blood measurements were obtained by retro-orbital sinus collection at the time points indicated. Collected blood was allowed to clot for 30 minutes before centrifugation for 10 minutes at 1000 × g. Serum was removed immediately and stored at -20°C until utilized. Cytokine serum levels were assayed with a Milliplex MAP Mouse Cytokine Magnetic Bead Panel (Millipore) and analysis was performed in the Center for AIDS Research ImmunoBioSpot Core Facility that is supported by National Institutes of Health awards CA-16042 and AI-28697, and by the UCLA AIDS Institute.
Total body irradiation
Financial support: This work was supported in part by NIH/NCI grants K01-CA111402 and RO1-CA123396 (to RMP), R01 CA 112358 (to LML), the Eli & Edyth Broad Center of Regenerative Medicine and Stem Cell Research at UCLA (to RMP and LML), the STOP Cancer Foundation (RMP), and the Ben & Catherine Ivy Foundation (to RMP). Flow cytometry was performed at the UCLA Jonsson Comprehensive Cancer Center (JCCC) Core Facility, which is supported by the NIH award CA16042. Multi-analyte serum profiling was performed at the Center for AIDS Research (CFAR) ImmunoBioSpot Core Facility, which is supported by National Institutes of Health awards CA-16042 and AI-28697, and by the UCLA AIDS Institute.
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