Complex Immunosuppressive Action of Farnesyltransferase Inhibitor (FTI) R115777 (Tipifarnib, Zarnestra®) with Induction of Apoptosis in T Cells from Patients with Large Granular Lymphocyte (LGL) Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4960-4960
Author(s):  
Fanqi Bai ◽  
JianXiang Zou ◽  
Jun Yang ◽  
Edna Ku ◽  
Sheng Wei ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Western Blot ◽  
Cd8 T Cells ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Large Granular Lymphocyte ◽  
Erk Signaling ◽  
Lgl Leukemia

Abstract BACKGROUND: Large Granular Lymphocyte (LGL) leukemia is an indolent clonal disorder arising from either CD3+ or CD3− immunophenotypes characterized as T-cell and Natural-Killer (NK)-cell malignancies, respectively. Due to a rare incidence, all therapeutic investigations in LGL leukemia are generated from single institution experiences, which consist primarily of retrospective cohort analyses. Pathogenesis may relate to an underlying autoimmune mechanism with low-dose methotrexate (10mg/m2 weekly), cyclophosphamide (50–100mg daily), and cyclosporine A (5–10mg/kg daily) used as first-line agents for the treatment of associated cytopenias. The mechanism(s) controlling survival of leukemic LGL are not fully characterized. We hypothesize that agents that target survival signaling will serve as effective therapeutics. Using pharmacologic inhibitors of the Mitogen Activated Protein Kinase (MAPK/ERK) signaling cascase, we found that ERK/Ras drives NK leukemia survival (Epling-Burnette, et al. Oncogene, 23:9220, 2004). The goal of this study was to investigate the in vitro actions of the farnysltransferase-inhibitor R115777 (tipifarnib, Zarnestra®, Johnson and Johnson) on survival and immune response leukemic T cells. METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from patients with T LGL leukemia. All patients had increased numbers of CD3+ αβ T lymphocytes and evidence of clonality. Western blot analysis was used to examine the protein levels of phosphorylated (active) ERK1 and ERK2 (MAPK), Bcl-2, and total MAPK. Apoptosis assays were performed by staining with annexin-V-FITC and 7-aminoactinomycin (7-AAD) and flow cytometry analysis. Anti-CD3 plus anti-CD28 was used to stimulate T cells in the presence of brefelden A and IL-2, IFN-γ, TNF-α, IL-4, and IL-10 were determined in distinct T cell subpopulations by intracellular staining. T cell proliferation was assessed by Brdu incorporation in CD4+ and CD8+ T cells. RESULTS: PBMCs from patients with T LGL displayed constitutively-active MAPK/ERK expression as determined by Western blot analysis (n=5). Using MEK pharmacological inhibitors, we found that blockade of the active MEK/ERK signaling pathway induced apoptosis in leukemic T LGL. Bcl-2 was expressed in 80% of patients and when MEK/ERK was inhibited there was a corresponding reduction in expression. Targeted disruption of farnesyl-transferase with two different inhibitors (FTI2153 and R115777, n=9) led to a dose-dependent increase in apoptosis with an apoptotic index that was significantly greater than normal T cells. In addition to apoptosis, we found that antigen-induced proliferation of CD4+ and CD8+ T cells was impaired by R115777 (11% ± 7 vs. 3% ±1.7 and 11% ± 9 vs. 3% ± 1.6, respectively). Furthermore, R115777 biased antigen-dependent cytokine response to a Th2 type with increased expressionof IL-4 and IL-10 after drug treatment (average increase 100% and 43%, respectively). CONCLUSIONS: These findings suggest that FTIs regulate immune response and lead to apoptosis of leukemic T LGL cells. A pilot trial of R115777 (tipifarnib, Zarnestra®) is ongoing for the treatment of LGL leukemia.

scholarly journals Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254243
Author(s):  
Meritxell Llorens-Revull ◽  
Maria Isabel Costafreda ◽  
Angie Rico ◽  
Mercedes Guerrero-Murillo ◽  
Maria Eugenia Soria ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Clearance ◽  
Cd4 T Cell ◽  
Care Hospital ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Background & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.

scholarly journals Divergent Impact of Glucose Availability on Human Virus-Specific and Generically Activated CD8 T Cells

Metabolites ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 461
Author(s):  
Jenifer Sanchez ◽  
Ian Jackson ◽  
Katie R. Flaherty ◽  
Tamara Muliaditan ◽  
Anna Schurich
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Cell Immune Response ◽  
Complex Nature ◽  
Human Virus ◽  
Glucose Availability

Upon activation T cells engage glucose metabolism to fuel the costly effector functions needed for a robust immune response. Consequently, the availability of glucose can impact on T cell function. The glucose concentrations used in conventional culture media and common metabolic assays are often artificially high, representing hyperglycaemic levels rarely present in vivo. We show here that reducing glucose concentration to physiological levels in culture differentially impacted on virus-specific compared to generically activated human CD8 T cell responses. In virus-specific T cells, limiting glucose availability significantly reduced the frequency of effector-cytokine producing T cells, but promoted the upregulation of CD69 and CD103 associated with an increased capacity for tissue retention. In contrast the functionality of generically activated T cells was largely unaffected and these showed reduced differentiation towards a residency phenotype. Furthermore, T cells being cultured at physiological glucose concentrations were more susceptible to viral infection. This setting resulted in significantly improved lentiviral transduction rates of primary cells. Our data suggest that CD8 T cells are exquisitely adapted to their niche and provide a reminder of the need to better mimic physiological conditions to study the complex nature of the human CD8 T cell immune response.

scholarly journals Anti–4-1bb Monoclonal Antibodies Abrogate T Cell–Dependent Humoral Immune Responses in Vivo through the Induction of Helper T Cell Anergy

1999 ◽  
Vol 190 (10) ◽  
pp. 1535-1540 ◽  
Author(s):  
Robert S. Mittler ◽  
Tina S. Bailey ◽  
Kerry Klussman ◽  
Mark D. Trailsmith ◽  
Michael K. Hoffmann
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cells ◽  
Humoral Immunity ◽  
Cd8 T Cells ◽  
Immunodeficient Mice ◽  
Humoral Immune

The 4-1BB receptor (CDw137), a member of the tumor necrosis factor receptor superfamily, has been shown to costimulate the activation of T cells. Here we show that anti–mouse 4-1BB monoclonal antibodies (mAbs) inhibit thymus-dependent antibody production by B cells. Injection of anti–4-1BB mAbs into mice being immunized with cellular or soluble protein antigens induced long-term anergy of antigen-specific T cells. The immune response to the type II T cell–independent antigen trinintrophenol-conjugated Ficoll, however, was not suppressed. Inhibition of humoral immunity occurred only when anti–4-1BB mAb was given within 1 wk after immunization. Anti–4-1BB inhibition was observed in mice lacking functional CD8+ T cells, indicating that CD8+ T cells were not required for the induction of anergy. Analysis of the requirements for the anti–4-1BB–mediated inhibition of humoral immunity revealed that suppression could not be adoptively transferred with T cells from anti–4-1BB–treated mice. Transfer of BALB/c splenic T cells from sheep red blood cell (SRBC)-immunized and anti–4-1BB–treated mice together with normal BALB/c B cells into C.B-17 severe combined immunodeficient mice failed to generate an anti-SRBC response. However, B cells from the SRBC-immunized, anti–4-1BB–treated BALB/c mice, together with normal naive T cells, exhibited a normal humoral immune response against SRBC after transfer, demonstrating that SRBC-specific B cells were left unaffected by anti–4-1BB mAbs.

T Large Granular Lymphocyte (LGL) Leukemia Characterized by Expansion of Terminal CD3+/CD8+/CD62L−/CD45RA+ Effector Memory T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4962-4962
Author(s):  
JianXiang Zou ◽  
Jeffrey S. Painter ◽  
Fanqi Bai ◽  
Thomas P. Loughran ◽  
P.K. Epling-Burnette
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Effector Memory ◽  
T Cell Proliferation ◽  
Normal Controls ◽  
Terminal Effector ◽  
Homeostatic Mechanisms ◽  
Lgl Leukemia

Abstract Background: Clonal proliferation by mature Large Granular Lymphocytes is associated with LGL leukemia. This expansion of CD3− NK cells or CD3+ T cells may be the result of chronic antigen stimulation by autoantigens or viral antigens. In association with T cell lymphoproliferation, approximately 45% of patients with LGL leukemia have severe neutropenia (absolute neutrophil count <0.5×109/L) and 20% of patients have transfusion-dependent anemia. Homeostatic mechanisms normally modulate the generation of naïve and memory T cell pools and regulate the T cell repertoire; however, the pathways elicited during T memory differentiation, maintenance and expansion are not fully characterized. The goal of this work was to characterize the homeostatic mechanisms that regulate LGL leukemia. Methods: Peripheral blood mononuclear cells were isolated from patients with LGL leukemia and normal controls. We performed multiplex TCR-Vβ (CDR3) PCR on cells from 16 LGL patients to identify clonal T cell proliferation. The percentage of CD3+ T cells that expressed each of the TCR-Vβ families was determined in 20 healthy donors to establish the mean and standard deviation (S.D.) of the control population. Naïve and memory CD4 and CD8 T cell sub-populations were segregated by expression of CD45RA and CD62L expression by flow cytometry and T cell proliferation was assessed by Brdu incorporation in CD4+ and CD8+ T cells. Results: The absolute number of CD4+ T cells was reduced in LGL patients compared to normal donors and T cell clones were characterized by a CD8+ phenotype. By flow cytometry, expansion of a single Vβ clonal population occurred in 8 of 16 patients (50%), two clones were present in 4 of 16 patients (25%), and three clones in 4 of 16 patients (25%). The immunophenotype of TCR Vβ+ clonal T cells was CD8 positive, CD57 positive, CD28 negative, CD25 negative, and NKG2D (NKG2-family) positive and CD244 (2B4) positive. Three patients examined expressed Killer-Immunoglobulin-like (KIR) receptors. Further phenotype analysis showed that there were fewer than normal CD4+ naïve (CD4+/CD45RA+/CD62L+) T cells (23%±16 vs. 41%± 15, P=0.04 by a t test) in LGL patients. CD4+ T cells from patients had reduced proliferation in response to antigen stimulation. The reduction in CD4+ naïve T cells was associated with increased percentages of CD4+/CD45RA−/CD62L+ central memory T cells (P<0.05). Reduced percentage of naive CD8+ T cells in detected in LGL leukemia patients. In addition, CD4+ central memory cells were also significantly reduced in patients. CD8+ T cells were primarily characterized by a CD45RA+/CD62L− terminal effector memory phenotype that was significantly increased compared to normal donors (mean 75% ± 13 in patients vs 30% ± 13 in normal controls, P<0.0001). In the presence of a skewed repertoire and terminal effector memory cell accumulation, antigen-induced proliferation of CD8+ T cells in LGL did not differ from normal controls (13% ± 11 in patients vs. 9% ± 3 in normal controls, P=0.3). Conclusions: These results suggest that leukemic LGL represent the accumulation of CD8+ terminal effector memory cells with the capacity for increased proliferation. Our findings suggest that normal homeostatic signals are impaired in LGL leukemia that limits the terminal CD8 differentiation phase of an immune response.

Generation of CD8 T Cell-Mediated Protective Immunity against Tumor Escapees

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2623-2623 ◽  
Author(s):  
Bindu Varghese ◽  
Behnaz Taidi ◽  
Adam Widman ◽  
James Do ◽  
R. Levy
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Cd8 T Cell

Abstract Introduction: Anti-idiotype antibodies against B cell lymphoma have shown remarkable success in causing tumor regression in the clinic. In addition to their known ability to mediate ADCC, anti-idiotype antibodies have also been shown to directly inhibit the proliferation of tumor cells by sending negative growth signals via the target idiotype. However, further studies to investigate this mechanism have been hindered by the failure of patient tumor cells to grow ex vivo. Methods and Results: In order to study this phenomenon further, we developed an antibody against the idiotype on an A20 mouse B lymphoma cell line. A radioactive thymidine incorporation assay showed decreased A20 cell proliferation in the presence of the anti-id antibody ex vivo. In vivo, when mice were treated intraperitoneally (i.p.) with 100 μg of antibody 3 hours post-tumor inoculation (1×106 A20 subcutaneously (s.c.)), tumor growth was delayed for greater than 40 days after which the tumor began to grow once again. Further analysis of these escaping tumor cells by flow cytometry showed that that the tumor cells escaped the antibody-mediated immune response by down-regulating expression of idiotype and IgG on their surfaces although the cells retained idiotype expression intracellularly. This down-regulation of surface idiotype rendered the tumor cells resistant to both ADCC and signaling-induced cell death. The addition of an immunostimulatory bacterial mimic (CpG-DNA; 100 μg × 5 intratumoral (i.t.) injections; Days 2, 3 4, 6 & 8) to antibody therapy (Day 0; 100 μg i.p.) cured large established tumors (Day 0 = 1 cm2) and prevented the occurrence of tumor escapees (p<0.0001). Antibody plus CpG combination therapy in tumor-bearing mice deficient for CD8+ T cells demonstrated the critical role of CD8+ T cells in A20 tumor eradication (p<0.005). Depletion of CD4+ T cells was found to have no significant impact on the therapy. We also found that when mice were inoculated with two tumors and treated with anti-idiotype antibody (i.p.) followed by intratumoral CpG in just one tumor (Day 0=1 cm2; anti-idiotype antibody 100 μg Day 0; 100 μg CpG Days 2, 3, 4, 6 & 8), untreated tumors regressed just as well as CpG-treated tumors indicating a systemic anti-tumor immune response was generated. Conclusion: Anti-idiotype therapy, although effective in delaying tumor growth, frequently generates antigen-loss variants. However, we found that when anti-idiotype antibodies were combined with CpG, even large established tumors were cured due to systemic CD8+ T cell-dependent tumor immunity. Rather than simply mediating ADCC against a single tumor antigen, which requires the constant infusion of antibody to hamper tumor growth, we hypothesize a cytotoxic T-cell response against many tumor antigens was also generated. Such a diverse T-cell repertoire can prevent the emergence of tumor escapees and collectively provide long-lasting tumor protection. These pre-clinical results suggest that anti-tumor antibodies combined with CpG warrant further study in patients with B cell lymphoma.

Autoproliferation Contributes to Clonal Expansion and Changes In Cellular Topography In T Cell Large Granular Lymphocyte (LGL) Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1373-1373
Author(s):  
JianXiang Zou ◽  
Jeffrey S Painter ◽  
Fanqi Bai ◽  
Lubomir Sokol ◽  
Thomas P. Loughran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Ki67 Expression ◽  
Terminal Effector ◽  
Lgl Leukemia

Abstract Abstract 1373 Introduction: LGL leukemia is associated with cytopenias and expansion of clonally-derived mature cytotoxic CD8+ lymphocytes. The etiology of LGL leukemia is currently unknown, however, T cell activation, loss of lymph node homing receptor L-selectin (CD62L), and increased accumulation of T cells in the bone marrow may lead to suppressed blood cell production. The broad resistance to Fas (CD95) apoptotic signals has lead to the hypothesis that amplification of clonal cells occurs through apoptosis resistance. However, the proliferative history has not been carefully studied. To define possible mechanism of LGL leukemia expansion, T cell phenotype, proliferative history, and functional-related surface marker expression were analyzed. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 16 LGL leukemia patients that met diagnostic criteria based on the presence of clonal aβ T cells and >300 cells/ml CD3+/CD57+ T cells in the peripheral blood. Samples were obtained from 10 age-matched healthy individuals from the Southwest Florida Blood Services for comparisons. Multi-analyte flow cytometry was conducted for expression of CD3, CD4/8, CD45RA, CD62L, CD27, CD28, CD25, CD127, IL15Ra, IL21a, CCR7 (all antibodies from BD Biosciences). The proliferative index was determined by Ki67 expression in fixed and permeabilized cells (BD Biosciences) and the proliferative history in vivo was assessed by T-cell-receptor excision circle (TREC) measurement using real-time quantitative PCR (qRT-PCR) in sorted CD4+ and CD8+ T cells. TRECs are episomal fragments generated during TCR gene rearrangements that fail to transfer to daughter cells and thus diminish with each population doubling that reflects the in vivo proliferative history. Results: Compared to healthy controls, significantly fewer CD8+ naïve cells (CD45RA+/CD62L+, 8.4 ± 10.8 vs 24.48 ± 11.99, p=0.003) and higher CD8+ terminal effector memory (TEM) T cells (CD45RA+/CD62L-, 67.74 ± 28.75 vs 39.33 ± 11.32, p=0.007) were observed in the peripheral blood. In contrast, the percentage of CD4+ naïve and memory cells (naïve, central memory, effector memory, and terminal effector memory based on CD45RA and CD62L expression) was similar in patients as compared to controls. The expression of CD27 (31.32 ± 34.64 vs 71.73 ± 20.63, p=0.003) and CD28 (31.38 ± 31.91 vs 70.02 ± 22.93, p=0.002) were lower in CD8+ T cell from patients with LGL leukemia and this reduction predominated within the TEM population (17.63±24.5 vs 70.98±22.5 for CD27, p<0.0001 and 13±20.5 vs 69.43± 21.59 for CD28, p<0.0001). Loss of these markers is consistent with prior antigen activation. There was no difference in CD25 (IL2Ra, p=0.2) expression on CD4+ or CD8+ T cells, but CD127 (IL7Ra, p=0.001), IL15Ra, and IL21Ra (p=0.15) were overexpressed in TEM CD8+ T cell in patients vs controls. All of these cytokine receptors belong to the IL2Rβg-common cytokine receptor superfamily that mediates homeostatic proliferation. In CD8+ T cells in patients, the IL-21Ra was also overexpressed in naïve, central and effector memory T cells. The topography of the expanded CD8+ T cell population was therefore consistent with overexpression of activation markers and proliferation-associated cytokine receptors. Therefore, we next analyzed Ki67 expression and TREC DNA copy number to quantify actively dividing cells and determine the proliferative history, respectively. We found that LGL leukemia patients have more actively dividing CD8+ TEM T cells compared to controls (3.2 ± 3.12 in patients vs 0.44 ± 0.44 in controls, p=0.001). Moreover, the TREC copy number in CD8+ T cells was statistically higher in healthy individuals after adjusting for age (177.54 ± 232 in patients vs 1015 ± 951 in controls, p=0.019). These results show that CD8+ cells in the peripheral compartment have undergone more population doublings in vivo compared to healthy donors. In contrast, the TREC copies in CD4+ T-cells were similar between LGL patients and controls (534.4 ± 644 in patients vs 348.78 ± 248.16 in controls, p>0.05) demonstrating selective cellular proliferation within the CD8 compartment. Conclusions: CD8+ T- cells are undergoing robust cellular activation, contraction in repertoire diversity, and enhanced endogenous proliferation in patients with LGL leukemia. Collectively, these results suggest that clonal expansion is at least partially mediated through autoproliferation in T-LGL leukemia. Disclosures: No relevant conflicts of interest to declare.

Combining chemotherapy and programmed death 1 (PD-1) blockade to induce a T-cell response in patients with metastatic triple negative breast cancer (mTNBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11563-11563 ◽  
Author(s):  
Elias Obeid ◽  
Chun Zhou ◽  
Alexander Macfarlane ◽  
R. Katherine Alpaugh ◽  
Cecilia McAleer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
T Cell Response ◽  
Number Of Patients ◽  
Correlative Studies ◽  
Immune Changes

11563 Background: Correlative studies to determine the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of a clinical trial in MTNB. The trial design is a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. One key concern is that CT may suppress immune cell function, thereby diminishing the efficacy of PD-1 blockade. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6-12 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Safety run-in consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8. Patients are consented for a peripheral blood (PB) collection pre-cycle 1 and on day 1 of cycle 3, in order to phenotype immune system changes by flow-cytometry. Results: Six patients have been recruited as of this interim analysis. Data from PB analysis of 3 on-treatment patients is available. In 2 subjects, the activation marker CD69 increased on CD4+ and CD8+ T cells from baseline, indicating enhanced T cell function. Also the ratio of CD8+ T cells to regulatory T cells (CD25high CD127low) has increased. Both patients expressed PD-1 on T cells at baseline. The 2 subjects with evidence for enhanced immune response have a continued clinical benefit (12 cycles subject 1, 8 cycles subject 2). In contrast, subject 3 (who discontinued P and received corticosteroids for grade a 2 immune-related hepatitis during cycle 2) lacked expression of PD-1 on T cells and did not exhibit these immune changes, and her disease clinically progressed after 4 cycles of CT. Conclusions: Although comprising a very limited number of patients, early analysis from our correlative studies of combining CT with the PD-1 blockade revealed evidence for effective immune stimulation in two subjects. Furthermore, immune changes accompanied a lasting clinical response. Although early, we conclude that combining CT with checkpoint blockade can achieve its goal of unleashing an anti-tumor immune response in mTNBC patients. Clinical trial information: NCT02755272.

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