Peripheral human CD4+CD8+ T lymphocytes exhibit a memory phenotype and enhanced responses to IL-2, IL-7 and IL-15

Clénet, Marie-Laure; Gagnon, François; Moratalla, Ana Carmena; Viel, Émilie C.; Arbour, Nathalie

doi:10.1038/s41598-017-11926-2

Cited by 62 publications

(51 citation statements)

References 54 publications

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“…There was, however, a statistically significant increase in CD44 expressing DP lymphocytes (Fig S6D). Compared to CD4 and CD8 mono-positive T cells, DP lymphocytes exhibit characteristics similar to memory T lymphocytes, have a higher capacity to produce cytokines, and improved lytic potential (31,32). Based on these observations we infer that DABIL-4 mediated depletion of immunosuppressive cell populations facilitates significant increases in the population of activated effector T cells in the TME.…”

Section: Dabil-4 Increases Effector T Cell Population and Their Cytotmentioning

confidence: 84%

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

Parveen

Siddharth

Kumar

et al. 2020

Preprint

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In many solid tumors including triple-negative breast cancer (TNBC), IL-4 receptor (IL-4R) upregulation has been shown to promote cancer cell proliferation, apoptotic resistance, metastatic potential and a Th2 response in the tumor microenvironment (TME). Immunosuppressive cells in the TME including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) also express the IL4-R. We hypothesized that selective depletion of IL4-R bearing cells in TNBC may have dual cytotoxic and immunotherapeutic benefit. To selectively target IL-4R+ cells, we genetically constructed, expressed and purified DABIL-4, a fusion protein toxin consisting of the catalytic and translocation domains of diphtheria toxin fused to murine IL-4. We found that DABIL-4 has potent and specific cytotoxic activity against TNBC cells in vitro. In murine TNBC models, DABIL-4 significantly reduced tumor growth, splenomegaly and lung metastases, and this was associated with reductions in MDSC, TAM and regulatory T-cells (Tregs) populations with a concomitant increase in the proportion of IFNγ+ CD8 T-cells. The anti-tumor activity of DABIL-4 was absent in IL-4R KO mice directly implicating IL-4R directed killing as the mechanism of anti-tumor activity. Moreover, NanoString analysis of DABIL-4 treated TNBC tumors revealed marked decline in mRNA transcripts that promote tumorigenesis and metastasis. Our findings demonstrate that DABIL-4 is a potent targeted antitumor agent which depletes both IL-4R bearing tumor cells as well as immunosuppressive cell populations in the TME.STATEMENT OF SIGNIFICANCEIn solid tumors like breast cancer, Interleukin-4 receptor (IL-4R) expression in the tumor microenvironment aids tumor growth and metastasis. IL-4R expression upon host immune cells further dampens antitumor immunity. In this study, we have genetically constructed a fusion protein toxin, DABIL-4, composed of the catalytic and translocation domains of diphtheria toxin and murine IL-4. DABIL-4 showed specific cytotoxicity against triple-negative breast cancer (TNBC) cells in vitro. DABIL-4 also markedly inhibited TNBC tumor growth and metastasis in vivo. The primary activity of DABIL-4 was found to be depletion of IL-4R+ immune cells in combination with direct elimination of tumor cells. In conclusion, DABIL-4 targeting of both tumor and immunosuppressive host cells is a versatile and effective treatment strategy for TNBC.

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Section: Dabil-4 Increases Effector T Cell Population and Their Cytotmentioning

confidence: 84%

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

Parveen

Siddharth

Kumar

et al. 2020

Preprint

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“…Previously, increased TNF‐α and IFN‐γ levels by PDT had been confirmed to create an immunogenic microenvironment against metastatic cancer . In addition, CD4 + CD8 + double positive T lymphocytes were correlated with enhanced TNF‐α and IFN‐γ production . In contrary to CAH (+), PD‐1 induced an enhancement in IFN‐γ secretion but not TNF‐α.…”

Section: Resultsmentioning

confidence: 92%

Robust Photodynamic Therapy Using 5‐ALA‐Incorporated Nanocomplexes Cures Metastatic Melanoma through Priming of CD4⁺CD8⁺ Double Positive T Cells

Wang

Deng

et al. 2019

Advanced Science

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Advanced melanoma can rarely be cured. Photodynamic therapy (PDT) readily eradicates the primary melanoma but has limited ability to destroy the spreading tumor cells unless supported by other combinative interventions to augment systemic antitumor immunity. Based on the previously synthesized penetration‐enhancing biomaterials, a topically administered nanoformulation is developed, which profoundly assists 5‐aminolevulinic acid (5‐ALA) in circumventing skin barrier to be selectively delivered to tumor cells. After endocytosis, accumulated 5‐ALA is efficiently metabolized to a photosensitizer protoporphyrin IX (PpIX) which stimulates a large production of cytotoxic reactive oxygen species (ROS) under illumination. Accompanied by the robust inflammatory responses followed by primary tumor destruction, CD4+CD8+ double positive T cells are highly boosted to harness host immunity to purge metastases in lymphoid organs. Compared with dacarbazine and programmed death 1 (PD‐1) antibody, this treatment in advanced melanoma murine models, achieves a striking curable rate of 90% without melanoma prognostic markers LDH and S‐100B detection, followed by a relapse‐free survival rate of 83.33% in 300 days. Moreover, the cured mice's immune system function recovers to an extent similar to healthy mice without prolonged or exaggerated inflammation. This study using the synergistic biomaterials approach may thus render 5‐ALA‐mediated PDT a potentially curative therapy for advanced melanoma in clinic.

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“…cruzi infection. CD4 + CD8 + T cells have been characterized as mature cells based on their expression of activation markers, their ability to respond to specific antigens and their capacity to migrate to inflamed tissues [ 30 , 32 ]. Consistent with these studies, the first aim of this work was to explore the frequency of this cellular population in chronic chagasic patients at different stages of disease and their functional characterization.…”

Section: Discussionmentioning

confidence: 99%

“…cruzi infection and is related to a mild form of Chagas disease [ 23 , 57 ]. It has been described that a greater proportion of CD4 + CD8 + T cells from healthy donors has an enhanced capacity to produce cytokines (such as IFN-γ, TNF-α, IL-2) and cytotoxic molecules (like perforin and granzyme B) compared to CD4 + and/or CD8 + T lymphocytes [ 30 ]. In the context of chronic infections, such as HIV, an increased production of IFN-γ by antigen-specific CD4 + CD8 + T cells has also been reported in comparison with other T cell populations [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent studies have characterized this cellular population in detail, but more information is still needed. Several groups have shown that CD4 + CD8 + T cells comprise mature T cells that are capable of being activated [ 29 – 32 ] and able to respond to specific antigen-producing cytokines and cytotoxic molecules and to migrate to inflamed tissues [ 30 – 32 ]. Thus, their role has been studied in viral chronic infectious diseases such as HIV [ 29 ] and HCV [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients

et al. 2018

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BackgroundChagas disease is caused by Trypanosoma cruzi. The persistence of the parasite is associated with the disease chronicity and the impairment of the cellular immune response. It has been reported that the CD4+CD8+ T cell population expands in chronic Chagas disease patients. Few studies have focused on this subset of cells, and very little is known about the impact of antiparasitic treatment on this population.MethodologyThirty-eight chronic Chagas disease patients (20 asymptomatic and 18 symptomatic) and twelve healthy controls were enrolled in this study. Peripheral blood mononuclear cells were stimulated with soluble T. cruzi antigens to analyze the production of cytokines and cytotoxic molecules by CD4+CD8+ T cells before and after benznidazole treatment. Additionally, expression and co-expression of five inhibitory receptors in these patients after treatment were studied using a multiparameter flow cytometry technique.Principal findingsThe frequency of CD4+CD8+ T cells was higher in chronic Chagas disease patients compared with healthy donors. Furthermore, a higher ratio of CD4+CD8low/CD4+CD8high subpopulations was observed in chronic Chagas disease patients than in healthy donors. Additionally, CD4+CD8+ T cells from these patients expressed and co-expressed higher levels of inhibitory receptors in direct proportion to the severity of the pathology. Benznidazole treatment reduced the frequency of CD4+CD8+ T cells and decreased the ratio of CD4+CD8low/CD4+CD8high subpopulations. The co-expression level of the inhibitory receptor was reduced after treatment simultaneously with the enhancement of the multifunctional capacity of CD4+CD8+ T cells. After treatment, an increase in the frequency of T. cruzi antigen-specific CD4+CD8+ T cells expressing IL-2 and TNF-α was also observed.ConclusionsCD4+CD8+ T cells could play an important role in the control of T. cruzi infection since they were able to produce effector molecules for parasite control. Benznidazole treatment partially reversed the exhaustion process caused by T. cruzi infection in these cells with an improvement in the functional response of the T. cruzi antigen-specific CD4+CD8+ T cells.

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Peripheral human CD4+CD8+ T lymphocytes exhibit a memory phenotype and enhanced responses to IL-2, IL-7 and IL-15

Cited by 62 publications

References 54 publications

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

Robust Photodynamic Therapy Using 5‐ALA‐Incorporated Nanocomplexes Cures Metastatic Melanoma through Priming of CD4⁺CD8⁺ Double Positive T Cells

Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients

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Peripheral human CD4+CD8+ T lymphocytes exhibit a memory phenotype and enhanced responses to IL-2, IL-7 and IL-15

Cited by 62 publications

References 54 publications

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

IL-4 receptor targeting as an effective immunotherapy against triple-negative breast cancer

Robust Photodynamic Therapy Using 5‐ALA‐Incorporated Nanocomplexes Cures Metastatic Melanoma through Priming of CD4+CD8+ Double Positive T Cells

Impact of benznidazole treatment on the functional response of Trypanosoma cruzi antigen-specific CD4+CD8+ T cells in chronic Chagas disease patients

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Robust Photodynamic Therapy Using 5‐ALA‐Incorporated Nanocomplexes Cures Metastatic Melanoma through Priming of CD4⁺CD8⁺ Double Positive T Cells