scholarly journals Tumoral PD-1hiCD8+ T cells are partially exhausted and predict favorable outcome in triple-negative breast cancer

2020 ◽  
Vol 134 (7) ◽  
pp. 711-726
Author(s):  
Liang Guo ◽  
Chunmei Cao ◽  
Shyamal Goswami ◽  
Xiaoyan Huang ◽  
Linxiaoxi Ma ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Triple Negative ◽  
Tissue Microarrays ◽  
T Cell Subsets ◽  
Cell Subpopulation ◽  
Molecular Features

Abstract Tumor-infiltrating PD-1hi dysfunctional CD8+ T cells have been identified in several tumors but largely unexplored in breast cancer (BC). Here we aimed to extensively explore PD-1hiCD8+ T cells in BC, focusing on the triple-negative BC (TNBC) subtype. Flow cytometry was used to study the phenotypes and functions of CD8+ T-cell subsets in peripheral blood and surgical specimens from treatment-naive BC patients. RNA-seq expression data generated to dissect the molecular features of tumoral PD-1neg, PD-1lo and PD-1hi CD8+ T cells. Further, the associations between tumoral PD-1hi CD8+ T cells and the clinicopathological features of 503 BC patients were explored. Finally, multiplexed immunohistochemistry (mIHC) was performed to evaluate in situ PD-1hiCD8+ T cells on the tissue microarrays (TMAs, n=328) for prognostic assessment and stratification of TNBC patients. PD-1hiCD8+ T cells found readily detectable in tumor tissues but rarely in peripheral blood. These cells shared the phenotypic and molecular features with exhausted and tissue-resident memory T cells (TRM) with a skewed TCR repertoire involvement. Interestingly, PD-1hiCD8+ T cells are in the state of exhaustion characterized by higher T-BET and reduced EOMES expression. PD-1hiCD8+ T cells found preferentially enriched within solid tumors, but predominant stromal infiltration of PD-1hiCD8+ T subset was associated with improved survival in TNBC patients. Taken together, tumoral PD-1hiCD8+ T-cell subpopulation in BC is partially exhausted, and their abundance signifies ‘hot’ immune status with favorable outcomes. Reinvigorating this population may provide further therapeutic opportunities in TNBC patients.

scholarly journals 94 Effects of chemoimmunotherapy on the peripheral blood: insights from immune monitoring of a phase Ib trial of pembrolizumab and paclitaxel or capecitabine for triple-negative breast cancer (TNBC)

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A103-A103
Author(s):  
Brie Chun ◽  
Joanna Pucilowska ◽  
Shu Ching Chang ◽  
Isaac Kim ◽  
Benjamin Nikitin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Triple Negative Breast Cancer ◽  
Peripheral Blood ◽  
Triple Negative ◽  
Early Stage ◽  
Medical Center ◽  
T Cell Subsets

BackgroundPembrolizumab plus curative-intent dose-dense anthracycline-based chemotherapy (ddAC) is associated with improved outcome in PD-L1-negative TNBC,1 whereas in the metastatic setting, clinical benefit of chemoimmunotherapy (taxane or gemcitabine/carboplatin) is restricted to PD-L1-positive patients.2 We hypothesize that this discordance could be related to immunomodulatory differences of the various chemotherapies. On-treatment serial monitoring of peripheral blood and tumoral T cells can be used to compare the effects of various regimens. We also hypothesize that T cell clonal expansion may differ across the regimens, and that tumor-enriched T cell clones are more likely to be tumor-reactive and expand following chemoimmunotherapy.MethodsBlood and tumor samples were collected from patients enrolled in a phase Ib clinical trial of palliative pembrolizumab and paclitaxel or capecitabine for metastatic TNBC, and from a contemporaneous cohort of patients treated with ddAC. T-cells were characterized using fresh whole blood flow cytometry and T-cell receptor (TCR) immunosequencing (immunoSEQ, Adaptive Biotechnologies) of DNA digests. Longitudinal regression was used to test the hypothesis that tumor-enriched T-cell clonotypes are more likely to expand in peripheral blood following therapy.ResultsWhen combined with pembrolizumab, paclitaxel versus capecitabine had similar effects on T-cells, resulting in a time-dependent lymphodepletion across all major T cell subsets (average CD3+ T cell fold-change capecitabine: -0.42, paclitaxel: -0.56, p = 0.80 t-test), whereas ddAC was associated with more profound lymphodepletion (CD3+ average fold-change: -1.21). Notably, ddAC was associated with higher odds of novel clonotype detection compared to capecitabine (odds ratio (OR): 3.42, 95% CI: 3.34–3.5) as well as compared to paclitaxel (OR: 1.53, 95% CI: 1.47–1.60). Significant expansion of tumoral clonotypes occurred in five patients receiving chemoimmunotherapy (average 4.2 unique clonotypes per patient, range 2–11). These clonotypes did not significantly expand over time in the blood. Similarly, T-cell clonotypes that were enriched within tumor did not exhibit measurable differences in serial trend within the peripheral blood.ConclusionsEffects to T cell subsets and clonotypes are similar between capecitabine and paclitaxel when combined with pembrolizumab. ddAC was more profoundly lymphotoxic, but resulted in greater clonotype expansion. These findings offer mechanistic insight onto the differences in clinical activity observed with chemoimmunotherapy in early stage versus metastatic TNBC. We observed no strong association between tumor clonotype enrichment and peripheral clonotype expansion, highlighting the unmet need to develop methods of monitoring tumor-reactive T cell clones in the context of immunotherapy.AcknowledgementsThe authors would like to acknowledge collaborators at the Earle A. Chiles Research Institute and Adaptive Biotechnologies for mentorship and guidance. Support for the clinical trial (NCT02734290), which comprised the metastatic cohort was provided by Merck and the Providence Opportunity Fund. Laboratory services were provided at no cost by Adaptive BiotechnologiesTrial RegistrationNCT02734290ReferencesSchmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020 Feb 27;382(9):810–821. doi: 10.1056/NEJMoa1910549.Cortes J, Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet 2020;396(10265):1817–1828. doi:10.1016/S0140-6736(20)32531-9Ethics ApprovalAll patients provided written, informed consent. The study protocols for the collection of specimens from the early-stage breast cancer cohort and from the metastatic TNBC clinical trial were separately approved by independent review boards at Providence Portland Medical Center and Cedars Sinai Medical Center (mTNBC clinical trial only).

Anti-Thymocyte Globulin (ATG) Differentially Depletes naïve and Memory T Cells and Permits Memory-Type Regulatory T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4670-4670
Author(s):  
Chang-Qing Xia ◽  
Anna Chernatynskaya ◽  
Clive Wasserfall ◽  
Benjamin Looney ◽  
Suigui Wan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Conflicts Of Interest ◽  
T Cell Subsets ◽  
Hematopoietic Stem

Abstract Abstract 4670 Anti-thymocyte globulin (ATG) has been used in clinic for the treatment of allograft rejection and autoimmune diseases. However, its mechanism of action is not fully understood. To our knowledge, how ATG therapy affects naïve and memory T cells has not been well investigated. In this study, we have employed nonobese diabetic mouse model to investigate how administration of anti-thymocyte globulin (ATG) affects memory and naïve T cells as well as CD4+CD25+Foxp3+ regulatory T cells in peripheral blood and lymphoid organs; We also investigate how ATG therapy affects antigen-experienced T cells. Kinetic studies of peripheral blood CD4+ and CD8+ T cells post-ATG therapy shows that both populations decline to their lowest levels at day 3, while CD4+ T cells return to normal levels more rapidly than CD8+ T cells. We find that ATG therapy fails to eliminate antigen-primed T cells, which is consistent with the results that ATG therapy preferentially depletes naïve T cells relative to memory T cells. CD4+ T cell responses post-ATG therapy skew to T helper type 2 (Th2) and IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) are less sensitive to ATG depletion and remain at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory-like immunophenotype is significantly increased in ATG-treated animals, which might play an important role in controlling effector T cells post ATG therapy. In summary, ATG therapy may modulate antigen-specific immune responses through modulation of naïve and memory T cell pools and more importantly through driving T cell subsets with regulatory activities. This study provides important data for guiding ATG therapy in allogenieic hematopoietic stem cell transplantation and other immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.

Effects of rhIL-7 administration in humans on in vivo expansion of naïve, memory and effector subsets of CD4+ & CD8+ T-cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2504-2504
Author(s):  
C. Sportes ◽  
F. Hakim ◽  
M. Krumlauf ◽  
R. Babb ◽  
T. Fleisher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Down Regulation ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Circulating Cells

2504 Background: IL-7 has a critical and non-redundant role in T-cell lymphopoiesis and peripheral T-cell homeostasis. IL-7 administration may prove clinically valuable in conditions of disease induced (HIV) or iatrogenic T-cell depletion and for modulation of vaccine immune responses. In the first phase I study in humans, recombinant human interleukin-7 (“CYT 99–007”, Cytheris Inc., Rockville, MD) was administered subcutaneously every other day for two weeks in adults with refractory malignancies at 3, 10, 30 and 60 μg/kg/dose. Biologic activity, defined as a 50% increase over baseline of peripheral blood CD3+ T-cells, was seen at and above the 10μg/kg/dose in all patients. The kinetics of proliferation and expansion of peripheral blood T-cell subsets were analyzed. Methods: Multicolor flow cytometry was performed at baseline, 1, 2 and 3 weeks. Among CD4+ cells, the most naïve were defined as CD45RA+ /CD31+. Among CD4+ & CD8+ cells, the main naïve, memory and effector populations were defined respectively as CD45RA+/CD27+, CD45RA-/CD27+ and CD45RA-/CD27-. Within each subset, the number of cells in cycle was defined by Ki67 staining. Results: Following IL-7 therapy, there was marked proliferation of all T-cells subsets, peaking at week 1, most striking for the naive subsets with 30–70% of circulating cells induced to cycle. Proliferation rates were halved by week 2 despite continuation of treatment, coincident with the observed down-regulation of the IL-7 receptor. Cycling returned to baseline by week 3. Significant proliferation was also induced in effector and memory CD4+ and CD8+ T-cells but to a lesser magnitude, resulting in a greater net expansion of the naïve subsets, still ongoing one week after the end of treatment. Conclusions: IL-7 administration induces marked expansion of naïve, memory and effector CD4+ & CD8+ T-cells in humans. Consistent with the known down-regulation of the IL-7 receptor upon IL-7 exposure, proliferation rates decrease during the second week of treatment. rhIL-7 induced T-cell expansion may prove clinically valuable in adoptive immunotherapy as an adjunct to tumor vaccination and / or immunorestorative agent. [Table: see text]

Chemotherapy to induce T-cell subpopulation changes in advanced breast cancer patients.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12562-e12562 ◽  
Author(s):  
Giuditta Comolli ◽  
Martina Torchio ◽  
Benvenuto Franceschetti ◽  
Irene Cassaniti ◽  
Ilario Rapposelli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Cd8 T Cells ◽  
Standard Dose ◽  
Cell Subpopulation ◽  
Breast Cancer Patients ◽  
Clinical Benefits ◽  
Pre Treatment

e12562 Background: Recent data suggest that some anti-cancer agents may generate a stimulation of the immune system that can account for additional clinical responses. In breast cancer (BC) the immunomodulation via chemotherapy (CT) opens possible clinical applications, but: a) the variability in the immune response requires a careful pt selection and b) monitoring immunocompetence in clinical routine still represents a technical challenge.Changes in sub-populations of cytotoxic (CD8+) T-cells (as reported in aging) are not well documented in cancer pts. Methods: We utilized multi-color immunophenotyping by flow cytometry (FCM) using a high-resolution whole-blood assay in 39 pts (median age 53; 34 - 74 yrs) with advanced BC undergoing first-line, standard-dose anthracycline/taxane-based CT and in 12 older healthy women, during a 6-months study, to analyze variations in CD8+ T-cells and the effects of CT on different T-cell sub-populations. Results: In all BC pts there was a consistent decrease in absolute numbers of lymphocytes, T-cells and CD8+ T-cells, starting from the first course and persisting during all the CT program. Among the T-cells, there was a lower CD8-/CD8+ ratio, persisting over 6 months, in pts compared to controls. The proportion of CD28-CD57+ cells also remained higher among pts throughout the sampling duration. The number of CD28+CD57- and CD28-CD5- cells decreased faster during CT than CD28+CD57+ and CD28-CD57+ cells, while only CD28-CD57- cells showed a significant reconstitutive capacity after 6 months.Anti-tumor CT in BC pts can produce clinical benefits also by restoring the responsiveness of T cells and by increasing the frequency and activation of tumor specific T-cells already present in blood before CT. Conclusions: Anthracycline/taxane-based CT is able to elicit changes in the pts immune system. These changes appeared to be pronounced in BC pts, with senescent CD8+ T-cells playing an important role. The pre-treatment condition was not restored after 6 months of CT. Multi-parameter FCM is a powerful tool for detailed analysis of the immune dysfunctions during CT and it will also help the development of combined schedules of CT plus new immunotherapeutic agents.

scholarly journals Bone Marrow NK1.1− and NK1.1+ T Cells Reciprocally Regulate Acute Graft versus Host Disease

1999 ◽  
Vol 189 (7) ◽  
pp. 1073-1081 ◽  
Author(s):  
Defu Zeng ◽  
David Lewis ◽  
Sussan Dejbakhsh-Jones ◽  
Fengshuo Lan ◽  
Marcos García-Ojeda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ifn Γ

Sorted CD4+ and CD8+ T cells from the peripheral blood or bone marrow of donor C57BL/6 (H-2b) mice were tested for their capacity to induce graft-versus-host disease (GVHD) by injecting the cells, along with stringently T cell–depleted donor marrow cells, into lethally irradiated BALB/c (H-2d) host mice. The peripheral blood T cells were at least 30 times more potent than the marrow T cells in inducing lethal GVHD. As NK1.1+ T cells represented <1% of all T cells in the blood and ∼30% of T cells in the marrow, the capacity of sorted marrow NK1.1− CD4+ and CD8+ T cells to induce GVHD was tested. The latter cells had markedly increased potency, and adding back marrow NK1.1+ T cells suppressed GVHD. The marrow NK1.1+ T cells secreted high levels of both interferon γ (IFN-γ) and interleukin 4 (IL-4), and the NK1.1− T cells secreted high levels of IFN-γ with little IL-4. Marrow NK1.1+ T cells obtained from IL-4−/− rather than wild-type C57BL/6 donors not only failed to prevent GVHD but actually increased its severity. Together, these results demonstrate that GVHD is reciprocally regulated by the NK1.1− and NK1.1+ T cell subsets via their differential production of cytokines.

Defining the Immune Checkpoint Landscape in the Bone Marrow and Peripheral Blood of Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2012-2012
Author(s):  
Nitin Jain ◽  
Sreyashi Basu ◽  
Beenu Thakral ◽  
Jan Burger ◽  
Philip A Thompson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Research Funding ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cd8 Cells ◽  
Checkpoint Receptors

Abstract Background: Limited data is available on expression levels of checkpoint receptors, respective ligands, and other immune markers in patients with CLL (Ramsay et al. Blood 2012). Checkpoint blockade has been a successful therapy of many cancers including melanoma, and more recently, Hodgkin's lymphoma. Understanding expression patterns of checkpoint receptors and ligands may help in the clinical development of checkpoint blockade as a therapy for patients with CLL. Methods: Between September 2015 and April 2016, we performed 17-color multi-parameter flow-cytometry (MFC) in paired peripheral blood (PB) and bone marrow (BM) samples from 30 patients with CLL who presented as new patients for evaluation at MDACC. Patients may have received prior CLL therapy. We evaluated expression of immune receptors (inhibitory receptors: PD1, CTLA4, LAG3, TIM3; activating receptors: GITR, OX40, 41BB, ICOS) on T cell subsets: CD4 T effector cells [Teff]: CD3+CD4+CD127lo/+Foxp3-, CD4 T regulatory cells [Treg]: CD3+CD4+CD127-Foxp3+, and CD8 T cells. CLL cells were assessed for both immune receptors (as above), and ligands (4-1BBL, B7-1, B7-2, ICOSL, PDL-1, PDL-2, OX40L). These analyses were performed on freshly collected PB and BM samples by the M. D. Anderson Cancer Center Immunotherapy Platform. Results: A total of 30 patients with CLL were enrolled. The median age was 66 years (range, 35-83). Nine were women. Nineteen were treatment-naive. Prognostic markers included FISH [del(17p) = 6; del(13q) = 9, del(11q) = 4, trisomy 12 = 3, negative = 8]. IGHV mutation status was available for 19 patients (13 unmutated IGHV, 6 mutated IGHV). B2M was ≥3.5 in 11 pts. Baseline expression of costimulatory receptors in CD8 T cells in the marrow, and of the ligands in CLL cells in the marrow is shown in Figure 1. In paired PB and BM sample analysis, there was a high correlation between expression level of PD1 on Treg (Pearson correlation, r = 0.90, p<0.00001), Teff (r = 0.87, p<0.00001), CD8+ cells (r = 0.80, p<0.00001), and CLL cells (r = 0.75, p<0.00001). PD-L1 expression on CLL cells was moderately correlated between PB and BM (r = 0.57, p<0.001). Patients with prior therapy had significantly higher expression of PDL1 on the CLL cells in both PB and BM (p=0.01 and p=0.002, respectively) compared to previously untreated patients. OX40 expression on CD8 cells was significantly higher in both PB and BM in previously treated patients (compared to previously untreated patients). Patients with unmutated IGHV (p = 0.003) and del17p (p = .03) had higher PDL1 expression on CLL cells in the marrow. Conclusions: There is a strong correlation in the expression levels of PD1 on various T cell subsets between PB and BM. Clinically targetable checkpoint receptors including PD1, OX40, CTLA4, and ICOS are consistently expressed across patients with CLL, and present on cells in both PB and BM. Disclosures Jain: BMS: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Infinity: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger:Roche: Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Gilead: Research Funding. Thompson:Pharmacyclics: Consultancy, Honoraria. Daver:Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding. Wierda:Acerta: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Novartis: Research Funding; Abbvie: Research Funding.

Decreases in Percentages of Naïve CD4 and CD8 T Cells and Increases in Percentages of Memory CD8 T-Cell Subsets in the Peripheral Blood Lymphocyte Populations of A-Bomb Survivors

2004 ◽  
Vol 161 (3) ◽  
pp. 290-298 ◽  
Author(s):  
Mika Yamaoka ◽  
Yoichiro Kusunoki ◽  
Fumiyoshi Kasagi ◽  
Tomonori Hayashi ◽  
Kei Nakachi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood Lymphocyte ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Blood Lymphocyte ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Memory Cd8 T Cell ◽  
Lymphocyte Populations

549 Characterizing double positive T cells in the tumor microenvironment: a tale of promiscuous cell fates

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A586-A586
Author(s):  
Sara Schad ◽  
Andrew Chow ◽  
Heng Pan ◽  
Levi Mangarin ◽  
Roberta Zappasodi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
Human Melanoma ◽  
B16 Melanoma ◽  
T Cell Subsets ◽  
Double Positive ◽  
Cell Fates ◽  
Single Positive

BackgroundCD4 and CD8 T cells are genetically and functionally distinct cell subsets of the adaptive immune system that play pivotal roles in immune surveillance and disease control. During development in the thymus, transcription factors ThPOK and Runx3 regulate the differentiation and maturation of these two lineages into single positive T cells that enter the periphery with mutually exclusive expression of either the CD4 or CD8 co-receptor.1–2 Despite our expectation that these two cell fates are fixed, mature CD4+CD8+ double positive (DP) T cells have been described in the context of numerous immunological responses, including cancer, but their molecular and functional properties and therapeutic relevance remain controversial and largely unknown.3–5MethodsOur lab has identified and characterized a heterogenous DP T cell population in murine and human melanoma tumors comprised of CD4 and CD8 T cells re-expressing the opposite co-receptor and a parallel uptake in the opposite cell type’s phenotype and function. Using CD4 (Trp1) and CD8 (Pmel) transgenic TCR T cells specific to B16 melanoma antigens gp75 and gp100 respectively, we demonstrate the re-expression of the opposite co-receptor following adoptive T cell transfer in B16 melanoma tumor bearing mice.ResultsSpecifically, up to 50% of transferred CD4 Trp1 T cells will re-express CD8 to become a DP T cell in the tumor microenvironment. Further, these CD4 derived DP T cells upregulate CD8 lineage regulator Runx3 and cytolytic genes Gzmb, Gzmk, and Prf1 to become potent cytotoxic T cells. Alternatively, a subset of CD8 Pmel T cells differentiate into DP T cells characterized by the increased expression of CD4, ThPOK, and regulatory marker FoxP3 (figure 1). In addition, we utilized 10x single cell and ATAC sequencing to further characterize these divergent DP T cell populations among open repertoire T cells isolated from murine and human melanoma tumors.ConclusionsOur findings highlight the capability of single positive T cells to differentiate in response to antigen and local stimuli into novel T cell subsets with polyfunctional characteristics. The resulting cell subsets will potentially affect the tumor microenvironment in distinct ways. Our studies may inform therapeutic approaches to identify antigen specific T cells as well as innovative signaling pathways to target when genetically engineering T cells to optimize cytotoxic function in the setting of adoptive cell therapy.Ethics ApprovalThe human biospecimen analyses were approved by Memorial Sloan Kettering Cancer Center IRB #06-107ReferencesEllmeier W, Haust L & Tschismarov R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cell Mol Life Sci 2013;70:4537–4553.Luckey MA, et al. The transcription factor ThPOK suppresses Runx3 and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling. Nature Immunology 2014; 15, 638–645.Bohner P, et al. Double positive CD4(+)CD8(+) T Cells are enriched in urological cancers and favor T Helper-2 polarization. Front Immunol 2019; 10, 622.Nascimbeni M, Shin E-C, Chiriboga L, Kleiner DE & Rehermann B. Peripheral CD4(+)CD8(+) T cells are differentiated effector memory cells with antiviral functions. Blood 2004;104:478–486.Nishida K, et al. Clinical importance of the expression of CD4+CD8+ T cells in renal cell carcinoma. Int Immunol 2020;32:347–357.

scholarly journals Quantitative assessment of the pool size and subset distribution of cytolytic T lymphocytes within human resting or alloactivated peripheral blood T cell populations.

1983 ◽  
Vol 158 (2) ◽  
pp. 571-585 ◽  
Author(s):  
A Moretta ◽  
G Pantaleo ◽  
L Moretta ◽  
M C Mingari ◽  
J C Cerottini
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Peripheral Blood ◽  
Great Majority ◽  
T Cell Subsets ◽  
Cytolytic T Lymphocytes ◽  
Subset Distribution

In order to directly assess the distribution of cytolytic T lymphocytes (CTL) and their precursors (CTL-P) in the two major subsets of human T cells, we have used limiting dilution microculture systems to determine their frequencies. The two subsets were defined according to their reactivity (or lack thereof) with B9.4 monoclonal antibody (the specificity of which is similar, if not identical, to that of Leu 2b monoclonal antibody). Both B9+ and B9- cells obtained by sorting peripheral blood resting T cells using the fluorescence-activated cell sorter (FACS) were assayed for total CTL-P frequencies in a microculture system that allows clonal growth of every T cell. As assessed by a lectin-dependent assay, approximately 30% of peripheral blood T cells were CTP-P. In the B9+ subset (which represents 20-30% of all T cells), the CTL-P frequency was close to 100%, whereas the B9- subset had a 25-fold lower CTL-P frequency. It is thus evident that 90% and 10% of the total CTL-P in peripheral blood are confined to the B9+ or B9- T cell subsets, respectively. Analysis of the subset distribution of CTL-P directed against a given set of alloantigens confirmed these findings. CTL-P frequencies were also determined in B9+ and B9- subsets derived from T cells that had been activated in allogenic mixed leucocyte cultures (MLC). Approximately 10% of MLC T cells were CTL-P. This frequency was increased 3.5-fold in the B9+ subset, whereas the B9- subset contained only a small, although detectable number of CTL-P. Moreover, the great majority of the (operationally defined) CTL-P in MLC T cell population were found to be directed against the stimulating alloantigens, thus indicating a dramatic increase in specific CTL-P frequencies following in vitro stimulation in bulk cultures.

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