189 A clear increase in TILs and modest tumor growth inhibition by pembrolizumab in prostate cancer tumors growing in bone of CD34+ engrafted NOG mice

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A203-A203
Author(s):  
Suominen Suominen ◽  
Justyna Zdrojewska ◽  
Jenni Mäki-Jouppila ◽  
Philip Dube ◽  
Ivan Gladwyn-Ng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Flow Cytometry ◽  
T Cells ◽  
Tumor Growth ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
List Type ◽  
X Ray ◽  
Bone Changes ◽  
Nog Mice

BackgroundThe recent KEYNOTE-199 trial raises hope for new treatment options for prostate cancer patients with the encouraging results of checkpoint inhibitor activity in a subset of prostate cancer patients, also including patients with bone-predominant disease. However, the patient subset that benefited from the treatment was small, needing identification predictive biomarkers1. Proper preclinical models can help in the biomarker quest as well as in the search and selection of the best possible combination partners for further clinical trials.MethodsIn this study the bone-metastatic disease was modeled by intratibial inoculation of LNCaP human prostate cancer cells to male CIEA NOG® (NOG) mice and NOG mice engrafted with human CD34+ hematopoietic stem cells (huNOG, Taconic Biosciences). Tumor growth was followed by serum PSA measurements and tumor-induced bone changes by X-ray images. At study week 4, the PSA positive mice were stratified to two groups (n=10) treated with IgG4 isotype control or pembrolizumab (5 mg/kg, i.p., Q5D) until the end of the study. Tumor-induced bone changes were followed by X-ray 4, 8 and 10 weeks after inoculation. The study was terminated 10 weeks after inoculation and tumors were processed for histological and immunohistochemical (IHC) analysis of tumor infiltrating lymphocytes (TILs). Changes in blood cell counts were assessed by flow cytometry and hematology (n=5/group).ResultsAt sacrifice, tumor-induced bone changes were observed in all mice, and there was no difference between the groups. Even though the PSA was not significantly lower in the pembrolizumab-treated group, the average histological tumorous surface was lower. In flow cytometry of peripheral blood, increases in the portions of CD3+ leukocytes and double positive CD4+CD8+ cells were observed, but no differences were found in CD4+ nor CD8+ T-cells. However, CD8+ T-cells were radically increased within the tumor as analyzed by IHC.ConclusionsThe model successfully mimicked the prevalent clinical situation, where clear responses in PSA or target lesions are not observed. However, a dramatic increase of cytotoxic T-cells in the tumor was observed, revealing the effects of pembrolizumab in a model of prostate cancer growth in bone of huNOG mice. The model presents a suitable platform for studying combination partners with pembrolizumab, that would boost or unlock the anti-tumor activity of the increased TILs.Ethics ApprovalThis study was approved by the National Animal Experiment Board in Finland; license number ESAVI-2331-04 10 07-2017.ReferenceAntonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol 2020;38:395–405.

Dysfunction of PSA-specific CD8+ T cells in prostate cancer patients correlates with CD38 and Tim-3 expression

2015 ◽  
Vol 64 (11) ◽  
pp. 1487-1494 ◽  
Author(s):  
Alberto Sada Japp ◽  
M. Alper Kursunel ◽  
Sarah Meier ◽  
Julia N. Mälzer ◽  
Xiangdong Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Cancer Patients ◽  
Cd8 T Cells

Prostate stem cell antigen: Identification of immunogenic peptides and assessment of reactive CD8+T cells in prostate cancer patients

2002 ◽  
Vol 102 (4) ◽  
pp. 390-397 ◽  
Author(s):  
Andrea Kiessling ◽  
Marc Schmitz ◽  
Stefan Stevanovic ◽  
Bernd Weigle ◽  
Kristina Hölig ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
Stem Cell ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Prostate Stem Cell Antigen ◽  
Cell Antigen ◽  
Immunogenic Peptides

500 P2RX7 agonist treatment boosts the ability of IL-12-activated CD8+ T cells to infiltrate and control murine melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A535-A535
Author(s):  
Kelsey Wanhainen ◽  
Stephen Jameson ◽  
Henrique Borges Da Silva
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Mitochondrial Respiration ◽  
Immune Cell ◽  
List Type ◽  
Memory Cd8 T Cells ◽  
And Control

BackgroundExtracellular adenosine triphosphate (eATP) is a ‘danger signal’ used to sense cellular damage, and recognized by purinergic receptors in mammals. Among those receptors, P2RX7 is preferentially expressed in immune cells. Notably, we recently discovered that P2RX7 is crucial for the generation and maintenance of long-lived tissue-resident and circulating memory CD8+ T cells.1 2 CD8+ T cell function is fundamental for tumor control, and therapies to harness protective CD8+ T cells that overcome exhaustion are currently in the limelight of anticancer strategies. Given our previous data, and the fact that eATP is abundantly present inside the melanoma microenvironment, we tested whether (a) P2RX7 is required for activated CD8+ T cells to infiltrate and control melanoma upon adoptive cell therapy, and (b) P2RX7 agonism can boost the anticancer capacity of CD8+ T cells.Methods(a) We in vitro-activated WT or P2rx7-/- CD8+ T cells (transgenic for the LCMV epitope gp33-P14 or for the ovalbumin SIINFEKL peptide-OTI) with anti-CD3/CD28/IL-2, ± IL-12, for 72h. Cells were adoptively transferred (single transfer of WT or P2rx7-/- cells) into mice with 7 days after subcutaneous transfer of B16 melanoma encoding gp33 or SIINFEKL. We tracked tumor growth until 60 days or at the appropriate endpoint. In some experiments, we sacrificed recipient mice 7 days after adoptive T cell transfer for immune cell phenotyping. Some parameters (cytokine production, mitochondrial respiration via Seahorse) were measured in in vitro-activated cells. (b) WT and P2rx7-/- cells were activated with anti-CD3/anti-CD28/IL-2, ± Bz-ATP, a P2RX7 agonist. Tumor growth was tracked over time until 60 days or at the appropriate endpoint.ResultsWT and P2RX7-deficient (P2rx7-/-) CD8+ T cells in the absence of IL-12 do not differ in tumor infiltration and/or control. However, P2rx7-/- CD8+ T cells activated in response to IL-12 tertiary stimulus do not control B16 melanomas as well as their WT counterparts. Phenotypically, IL-12-P2rx7-/- CD8+ T cells do not profoundly differ from IL-12-WT CD8+ T cells, except for diminished mitochondrial respiration levels in vitro, and diminished mitochondrial membrane potential (e.g. mitochondrial health) among tumor-infiltrating cells. Strikingly, Bz-ATP treatment increased the mitochondrial activity of WT CD8+ T cells in vitro and in vivo and led to increased B16 infiltration and control, in a P2RX7-dependent manner.ConclusionsWe are currently studying the mechanisms behind the ability of P2RX7 agonists to increase the antitumor function of CD8+ T cells; these are promising results that can lead to a new alternative in immune cell therapies against melanoma.AcknowledgementsWe would like to thank Jane Ding and Lily Qian for technical assistance, and Kristin Hogquist for scientific input.Ethics ApprovalThis study was approved by the IACUC board at the University of Minnesota (IACUC number A3456-01)ReferencesBorges da Silva H, Beura LK, Wang H, Hanse EA, Gore R, Scott MC, Walsh DA, Block KE, Fonseca R, Yan Y, Hippen KL, Blazar BR, Masopust D, Kelekar A, Vulchanova L, Hogquist KA, Jameson SC. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature. 2018; 559(7713):264–268.Borges da Silva H, Peng C, Wang H, Wanhainen KM, Ma C, Lopez S, Khoruts A, Zhang N, Jameson SC. Extracellular ATP sensing via P2RX7 promotes CD8+ tissue-resident memory T cells by enhancing TGF-β sensitivity. Immunity 2020;53(1):158–171.

scholarly journals Maturation of T and B Lymphocytes in the Assessment of the Immune Status in COVID-19 Patients

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2615
Author(s):  
Iwona Kwiecień ◽  
Elżbieta Rutkowska ◽  
Krzysztof Kłos ◽  
Ewa Więsik-Szewczyk ◽  
Karina Jahnz-Różyk ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Lymphocytes ◽  
Cd8 T Cells ◽  
X Ray ◽  
Healthy Control ◽  
Chest X Ray ◽  
Novel Coronavirus ◽  
And Control ◽  
B And T Lymphocytes

Cell response to novel coronavirus disease 19 (COVID-19) is currently a widely researched topic. The assessment of leukocytes population and the maturation of both B and T lymphocytes may be important in characterizing the immunological profile of COVID-19 patients. The aim of the present study was to evaluate maturation of B and T cells in COVID-19 patients with interstitial lesions on chest X-ray (COVID-19 X-ray (+)), without changes on X-ray (COVID-19 X-ray (−)) and in healthy control. The study group consisted of 23 patients divided on two groups: COVID-19 X-ray (+) n = 14 and COVID-19 X-ray (−) n = 9 and control n = 20. The flow cytometry method was performed. We observed a significantly higher percentage of plasmablasts and lower CD4+ lymphocytes in COVID-19 X-ray (+) patients than in COVID-19 X-ray (−) and control. In the COVID-19 X-ray (+) patients, there was a lower proportion of effector CD4+ T cells, naïve CD8+ T cells and higher central memory CD4+ cells and effector CD8+ T cells than control. The above results showed that the assessment of selected cells of B and T lymphocytes by flow cytometry can distinguish patients with COVID-19 and differentiate patients with and without changes on chest X-ray.

scholarly journals Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy

2021 ◽  
Vol 9 (1) ◽  
pp. e000832
Author(s):  
Anastasia Prokopi ◽  
Christoph H Tripp ◽  
Bart Tummers ◽  
Florian Hornsteiner ◽  
Sarah Spoeck ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Cd8 T Cells ◽  
Checkpoint Blockade ◽  
Tumor Stages ◽  
Tumor Immunogenicity

BackgroundImmunotherapy with checkpoint inhibitors has shown impressive results in patients with melanoma, but still many do not benefit from this line of treatment. A lack of tumor-infiltrating T cells is a common reason for therapy failure but also a loss of intratumoral dendritic cells (DCs) has been described.MethodsWe used the transgenic tg(Grm1)EPv melanoma mouse strain that develops spontaneous, slow-growing tumors to perform immunological analysis during tumor progression. With flow cytometry, the frequencies of DCs and T cells at different tumor stages and the expression of the inhibitory molecules programmed cell death protein-1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) on T cells were analyzed. This was complemented with RNA-sequencing (RNA-seq) and real-time quantitative PCR (RT-qPCR) analysis to investigate the immune status of the tumors. To boost DC numbers and function, we administered Fms-related tyrosine 3 ligand (Flt3L) plus an adjuvant mix of polyI:C and anti-CD40. To enhance T cell function, we tested several checkpoint blockade antibodies. Immunological alterations were characterized in tumor and tumor-draining lymph nodes (LNs) by flow cytometry, CyTOF, microarray and RT-qPCR to understand how immune cells can control tumor growth. The specific role of migratory skin DCs was investigated by coculture of sorted DC subsets with melanoma-specific CD8+ T cells.ResultsOur study revealed that tumor progression is characterized by upregulation of checkpoint molecules and a gradual loss of the dermal conventional DC (cDC) 2 subset. Monotherapy with checkpoint blockade could not restore antitumor immunity, whereas boosting DC numbers and activation increased tumor immunogenicity. This was reflected by higher numbers of activated cDC1 and cDC2 as well as CD4+ and CD8+ T cells in treated tumors. At the same time, the DC boost approach reinforced migratory dermal DC subsets to prime gp100-specific CD8+ T cells in tumor-draining LNs that expressed PD-1/TIM-3 and produced interferon γ (IFNγ)/tumor necrosis factor α (TNFα). As a consequence, the combination of the DC boost with antibodies against PD-1 and TIM-3 released the brake from T cells, leading to improved function within the tumors and delayed tumor growth.ConclusionsOur results set forth the importance of skin DC in cancer immunotherapy, and demonstrates that restoring DC function is key to enhancing tumor immunogenicity and subsequently responsiveness to checkpoint blockade therapy.

scholarly journals P03.31 Skin dendritic cells in melanoma are key for successful checkpoint blockade therapy

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A35.2-A36
Author(s):  
N Prokopi ◽  
CH Tripp ◽  
B Tummers ◽  
JC Crawford ◽  
M Efremova ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Mouse Model ◽  
Tumor Growth ◽  
Tumor Immunity ◽  
Cd8 T Cells ◽  
Checkpoint Blockade ◽  
And Function

BackgroundImmunotherapy of cancer by checkpoint blockade has significantly improved the survival of melanoma patients. However, in patients with tumors that are poorly infiltrated by effector T cells the clinical results are not encouraging. Therefore, combination approaches that enhance pre-existing anti-tumor immunity and reset the patients‘ immunological status are urgently needed. In this study we used the tg(Grm1)EPv melanoma mouse model that reflects a non-immunogenic tumor microenvironment. In this mouse model, spontaneous melanoma development is driven by the ectopic expression of the metabotropic glutamate receptor-1 in melanocytes, which confers to them a hyperproliferative and anti-apoptotic phenotype. The same alteration has been shown to be present in 40% of melanoma patient samples. The aim of our study was to investigate whether enhancing dendritic cell (DC) numbers and function in the tg(Grm1)EPv mouse model could restore responsiveness to checkpoint blockade.Material and MethodsWe used multicolor flow cytometry, gene expression analysis by RNA-seq and microarray to analyze tumors and tumor-draining lymph nodes (tdLN). With various immunological in vitro and in vivo assays we determined the functional role of DC in tumor immunity.ResultsA loss of skin DC has previously been reported for primary melanoma lesions and we here show that melanoma progression in the tg(Grm1)EPv mouse model coincides with a gradual decrease in the skin cDC2 subset and an upregulation of the inhibitory ligands PD-L1 and galectin-9. Monotherapy with anti-PD-L1 could not delay tumor growth, suggesting that this is a good model to study resistance to checkpoint blockade. We hypothesized that by boosting DC numbers and function we would restore responsiveness to checkpoint blockade. By administering a treatment consisting of systemic Flt3L and intratumoral polyI:C/anti-CD40, we were able to rescue the numbers and function of skin cDC2. Analysis of the treated tumors by flow cytometry showed that the DC boost regimen led to an increased tumor infiltration of activated CD4+ and CD8+T cells. An in vitro T cell proliferation assay revealed that dermal cDC2 that had migrated to the tdLN, played a crucial role in this process, since these were able to cross-present endogenous gp100 antigen more efficiently than migratory Langerhans cells and dermal cDC1. CD4+ and CD8+T cells recruited in the tumors of the DC boost treated mice, expressed PD-1 and TIM-3. Therefore, combination therapy with checkpoint blockade of these molecules resulted in increased cytotoxic activity within the tumor and eventually delay of tumor growth.ConclusionsOur results demonstrate that skin DC shape the tumor microenvironment upon immunotherapy and thus, therapies that aim to enhance responsiveness to checkpoint blockade may well benefit from a component that boosts the numbers and the function of skin DC.Disclosure InformationN. Prokopi: None. C.H. Tripp: None. B. Tummers: None. J.C. Crawford: None. M. Efremova: None. K. Hutter: None. L. Bellmann: None. G. Cappellano: None. L. Boon: None. D. Ortner: None. Z. Trajanoski: None. S. Chen: None. T. de Gruijl: None. D.R. Green: None. P. Stoitzner: None.

scholarly journals Pre-existing intratumoral CD8 T cells substantially contribute to control tumors following therapeutic anti-CD40 and polyI:C based vaccination

2020 ◽  
Author(s):  
Aaron D. Stevens ◽  
Timothy N.J. Bullock
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Tumor Control ◽  
Cell Trafficking ◽  
T Cell Trafficking ◽  
Cell Numbers

ABSTRACTBackgroundDendritic cells are potently activated by the synergistic action of CD40 stimulation in conjunction with signaling through toll like receptors, subsequently activating antigen specific T cells. Cancer vaccines targeting the activation of dendritic cells in this manner show promise in murine models and are being developed for human cancer patients. While vaccine efficacy has been established, further investigation is needed to understand the mechanism of tumor control and how vaccination alters tumor infiltrating immune cells.MethodsMice bearing established murine melanoma tumors were vaccinated with agonist anti-CD40, polyI:C, and tumor antigen. Intratumoral T cell numbers, differentiation state, proliferation, and survival were assessed by flow cytometry. T cell effector function was measured both within the tumor and ex vivo by flow cytometry. T cell trafficking was blocked to examine changes to intratumoral T cells present at the time of vaccination.ResultsVaccination led to increased intratumoral T cell numbers and delayed tumor growth. Expansion of T cells and tumor control did not require trafficking of T cells from the periphery. The increase in intratumoral T cells was associated with an acute burst in proliferation but not changes in viability. Intratumoral T cells had lower PD-1 and Eomes expression but were less functional after vaccination on a per cell basis. However, the increased intratumoral T cell numbers yielded increased effector T cells per tumor.ConclusionsPre-infiltrated CD8 T cells are responsive to CD40/TLR-mediated vaccination and sufficient for vaccination to delay tumor growth when additional T cell trafficking is blocked. This indicates that the existing T cell response and intratumoral DC could be critical for vaccination efficacy. This also suggests that circulating T cells may not be an appropriate biomarker for vaccination efficacy.

scholarly journals 275 Flow cytometry and nanoString provide a comprehensive cell- and gene-based tumor profile following checkpoint inhibition in a murine bladder cancer model

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A298-A298
Author(s):  
David Draper ◽  
Philip Lapinski ◽  
Scott Wise
Keyword(s):  
Flow Cytometry ◽  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Cd8 T Cells ◽  
Combination Treatment ◽  
Immune Gene ◽  
Cell Recruitment ◽  
Anti Tumor Activity

BackgroundBladder cancer (BC) is the thirteenth leading cause of cancer-related deaths.1 Five checkpoint immunotherapies that target the PD-1/PD-L1 axis are FDA approved, and gene- and protein-based approaches are helping to identify new combination treatment strategies for therapeutic intervention.2 Using the murine MB49 model for BC, we demonstrate how non-targeted immune gene expression profiling can combine with flow cytometry to provide a gene and cell-specific signature for the tumor microenvironment and help identify potential targets for novel treatment approaches.MethodsAnimals with established MB49 tumors were treated with anti-mPD-1 or isotype control antibodies. Tumors were collected 7 days after the last treatment. Flow cytometry examined anti-mPD-1 treatment-induced immunophenotypic modulation for eleven tumor-infiltrating immune subsets. The mouse PanCancer IO 360™ panel (NanoString) provided transcriptomic analysis of 770 immuno-oncology-related genes. The ROSALIND™ platform (OnRamp BioInformatics) was used to identify differentially regulated genes between treatment groups (±1.5 fold-change; p <0.05).ResultsAnti-mPD-1 had moderate anti-tumor activity, with a 58% tumor growth inhibition at day 18 post-implant in treated compared to control animals. Flow cytometry revealed anti-mPD-1 triggered an increase in tumor-infiltrating CD8+ T cells (45%) compared to control animals. Furthermore, the CD8+ T cell phenotype was altered by anti-mPD-1 treatment. The percentage of CD8+ T cells that expressed ICOS and LAG-3 was increased in tumors from anti-mPD-1 treated animals (22% and 35% respectively). A reduction in PD-1 expression was also observed (33%). In myeloid cells, iNOS expression increased in tumor-associated macrophages from treated animals compared to controls. NanoString analysis revealed 62 genes were differentially regulated in tumors from anti-mPD-1 treated animals compared to controls. ROSALIND analysis classified 30 of the genes as regulators of interferon, cytotoxicity, antigen presentation, and cytokine/chemokine signaling. Also, among the genes upregulated by anti-mPD-1 were IDO, HAVCR2 (TIM-3), and CSFR1, which can promote tumor growth and are clinical targets actively being investigated for new immunotherapies.ConclusionsNanoString analysis complemented flow cytometry to provide a comprehensive profile of the MB49 tumor. Together, these data demonstrate that anti-mPD1 increases T cell recruitment into the tumor and upregulates the expression of genes known to enhance T cell recruitment and anti-tumor activity. iNOS protein upregulation indicates that anti-mPD-1 treatment may also exert effects by reprogramming M2 macrophages towards an M1 phenotype. Upregulation of IDO, HAVCR2, and CSFR1 genes may effectively counteract anti-mPD-1 treatment. Further investigation may elucidate clinical implications for inhibitors of these gene products as combination treatment partners with anti-mPD-1.ReferencesSaginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A. Epidemiology of bladder cancer. Med Sci 2020;1:15–26. Lopez-Beltran A, Cimadamore A, Blanca A, Massari F, Vau N, Scarpelli M, Cheng L, Montironi R. Immune checkpoint inhibitors for the treatment of bladder cancer. Cancers 2021;1:131–146.Ethics ApprovalN/A

263 Pleiotropic effects of IL-7 in prostate cancer patients receiving Sipuleucel-T vaccination

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A287-A287
Author(s):  
Caroline Duault ◽  
Nirasha Ramchurren ◽  
Russell Pachynski ◽  
Lawrence Fong ◽  
Sean Bendall ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cancer Patients ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Therapeutic Potential ◽  
Intracellular Cytokine Staining ◽  
Γδ T Cells

BackgroundSipuleucel-T (Provenge) is the first therapeutic vaccination approved by the FDA so far, indicated for advanced metastatic prostate cancer patients. Despite an improvement of the overall survival, the benefits of the therapy are still short-term so increasing the duration of the efficacy is necessary. Specifically, T-cell anergy is one of the challenges that we need to overcome to improve the overall efficacy. IL-7 is known to promote the naive T cell activation and to increase the proliferation and activation of the T cell memory subsets. Therefore, in this phase II clinical trial, we tested the therapeutic potential of a human recombinant glycosylated IL-7 after completion of the Provenge therapy on asymptomatic advanced prostate cancer patients.MethodsTo get a comprehensive analysis of the immune landscape in these patients, we performed CyTOF analysis on PBMC samples obtained at week 1 (baseline) and week 6 after the beginning of the IL-7 therapy. After stimulation with PMA/Ionomycin, we proceeded to surface and intracellular cytokine staining before acquisition on the CyTOF. The data were then analyzed by expert gating on Cytobank.ResultsAt 6 weeks post therapy, our data showed an increase in the number of circulating T lymphocytes in the IL-7 cohort, especially CD8 T cells, in accordance with previous literature. Even though of the frequency of CD4 T cells did not increase, the cells showed greater functionalities, with increased expression of IL-2, TNFα and IL-6 upon stimulation by PMA-Ionomycine. Cytotoxic subsets were also positively affected, with increased expression of IFNγ in CD8 T cells, TNFα in NK cells and IL-2 in γδ T cells. Moreover, PD-1 expression was decreased on CD4, CD8 and γδ T cells while CD137 increased on CD4, CD8 and NK cells. In addition, despite a reduction in the pool of circulating monocytes, we observed higher TNFα expression in these cells.ConclusionsAltogether, our data revealed multiple effects of IL-7 in these patients, highlighting a complex set of in vivo mechanisms. In the future, knowledge of these effects may help in choosing the best agents to use in combination with IL-7 and/or the best patients to benefit from IL-7 as part of their therapeutic approach.Trial RegistrationNCT01881867Ethics ApprovalThe study was last approved by Fred Hutchinson Cancer Research Center Institutional Review Board, IR file 8037, on January 23, 2020

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