Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4+ T Cells

Muraro, Elena; Merlo, Anna; Martorelli, Debora; Cangemi, Michela; Santa, Silvia Dalla; Dolcetti, Riccardo; Rosato, Antonio

doi:10.3389/fimmu.2017.00197

Cited by 32 publications

(34 citation statements)

References 228 publications

(299 reference statements)

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“…In line with this concept, Pedersen and colleagues also reported high expression of human leucocyte antigen class II in OVCA patient biopsies, suggesting the involvement of CD4+ T cells in antitumor immunity in this indication. 10 Cytotoxic CD4+ T cells also play a major role in eliminating virus-infected cells 49 and, since they can be present in the expanded TIL product, they could have had played a role in the reactivity seen here.…”

Section: Discussionmentioning

confidence: 95%

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Santos

Heiniö

Cervera-Carrascón³

et al. 2020

J Immunother Cancer

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BackgroundOvarian cancers often contain significant numbers of tumor-infiltrating lymphocytes (TILs) that can be readily harnessed for adoptive T-cell therapy (ACT). However, the immunosuppressive ovarian tumor microenvironment and lack of tumor reactivity in TILs can limit the effectiveness of the therapy. We hypothesized that by using an oncolytic adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) to deliver tumor necrosis factor alpha (TNFa) and interleukin-2 (IL-2), we could counteract immunosuppression, and enhance antitumor TIL responses in ovarian cancer (OVCA).MethodsWe established ex vivo tumor cultures freshly derived from patients with advanced OVCA and evaluated the effects of Ad5/3-E2F-D24-hTNFa-IRES-hIL2 or Ad5/3-E2F-D24 (the control virus without TNFa and IL-2) on TILs, cytokine response and tumor viability. Tumor reactivity was assessed by determining interferon gamma (IFNg) response of clinically relevant TILs towards autologous T-cell-depleted ex vivo tumor cultures pretreated with or without the aforementioned oncolytic adenoviruses.ResultsTreatment of ex vivo tumor cultures with Ad5/3-E2F-D24-hTNFa-IRES-hIL2 caused a substantial rise in proinflammatory signals: increased secretion of IFNg, CXCL10, TNFa and IL-2, and concomitant activation of CD4+ and CD8+ TILs. Potent tumor reactivity was seen, as clinically relevant TIL secreted high levels of IFNg in response to autologous T-cell-depleted ovarian ex vivo tumor cultures treated with Ad5/3-E2F-D24-hTNFa-IRES-hIL2. This phenomenon was independent of PD-L1 expression in tumor cells, a factor that determined the variability of IFNg responses seen in different patient samples.ConclusionsOverall, oncolytic adenovirus Ad5/3-E2F-D24-hTNFa-IRES-hIL2 was able to rewire the ovarian tumor microenvironment to accommodate heightened antitumor TIL reactivity. Such effects may improve the clinical effectiveness of ACT with TILs in patients with advanced OVCA.

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Section: Discussionmentioning

confidence: 95%

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Santos

Heiniö

Cervera-Carrascón³

et al. 2020

J Immunother Cancer

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“…These latter two proteins are transcription factors that play a pivotal and synergic role in functional T‐cell differentiation. T‐Bet skews polarization of CD4+Th0 T‐cells into CD4+Th1 T‐cells and of naıve CD8+ T‐cells into effector cytotoxic T lymphocytes (CTLs) whereas eomesodermin stimulates the differentiation of CD8+ T‐cells into “virtual memory” CD8+ T‐cells and of CD4+Th1 T‐cells into CD4+ CTLs . CD4+ CTLs are a subset of CD4+ Th1 T‐cells that exert their cytotoxic function by means of the perforin‐granzyme pathway .…”

Section: Discussionmentioning

confidence: 99%

“…T‐Bet skews polarization of CD4+Th0 T‐cells into CD4+Th1 T‐cells and of naıve CD8+ T‐cells into effector cytotoxic T lymphocytes (CTLs) whereas eomesodermin stimulates the differentiation of CD8+ T‐cells into “virtual memory” CD8+ T‐cells and of CD4+Th1 T‐cells into CD4+ CTLs . CD4+ CTLs are a subset of CD4+ Th1 T‐cells that exert their cytotoxic function by means of the perforin‐granzyme pathway . GEP and eomesodermin evaluation by immunohistochemistry were not performed in our case; however, despite the lack of these data and because several studies refer a good correlation between molecular signature and protein expression detected by immunohistochemistry, we hypothesize that the immunoprofile of the tumor cells of the present report (Table ) is very similar to the aforementioned subset of PTCL‐NOS and to CD4+ CTLs …”

Section: Discussionmentioning

confidence: 99%

Activated‐cytotoxic TCRαβ+CD4+ peripheral T‐cell lymphoma with hypodermal localization: Case report of a lymphoproliferative disorder probably evolved from the CD4+ cytotoxic T‐cell subpopulation

et al. 2019

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The World Health Organization (WHO) classification of hematopoietic and lymphoid tumors identifies distinctive subtypes of peripheral T-cell lymphoma (PTCL), and, additionally, some PTCLs involving mostly extranodal sites like the skin. The difficulty of classifying PTCLs according to the normal stages of T-cell differentiation and the lack of definitive diagnostic markers for most of the subtypes make the diagnosis of these diseases challenging. PTCL cases which do not fit into any of the specifically defined entities are categorized as PTCL not otherwise specified (PTCL-NOS). PTCLs-NOS represent less than 2% of the total cases of T-cell lymphoma involving the skin. This article illustrates a case of a PTCL-NOS in which tumor cells have an activated cytotoxic TCRαβ+CD3+CD4+CD56+ T-cell phenotype and histopathologic features of subcutaneous panniculitis-like T-cell lymphoma, leading to a fatal outcome. K E Y W O R D S cutaneous T-cell lymphoma, dermatopathology, hematopathology, T-cell receptor rearrangement, T lymphocytes

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“…Specifically, infection with some viral pathogens including HIV [14] and hepatitis viruses [2,[15][16][17] havebeennoted to influencecharacteristics ofCD4 T lymphocyte cells.…”

Section: Cc-by-nc-ndmentioning

confidence: 99%

Assessment of CD4 T Lymphocyte Cell Levels among Hepatitis B, C and E Viruses Negative Individuals in Ibadan, southwestern Nigeria

Adewumi

Omoruyi

Ifeora

et al. 2017

Preprint

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The CD4 T lymphocytes play a key role in achieving a regulated effective immune response to foreign antigens. It is also a valuable parameter for assessing HIV disease progression. However, variations in CD4 T lymphocyte values due to diverse factors have been reported. We evaluated CD4 T lymphocytes among healthy community dwellers who tested negative for hepatitis B, hepatitis C and hepatitis E viruses and compared the results with the National Reference Values (NRVs). Four hundred consenting participants who fulfilled the criteria for enrolment were evaluated for CD4 T lymphocyte counts. Estimated mean CD4 T lymphocyte count of 1,183 (CD4 Range: 328-2680) cells/μl of blood was recorded for the participants. Four (1.0%), 151 (37.8%), 157 (39.2%), 74 (18.5), and 14 (3.5) of the participants had CD4 T lymphocyte count ranged 352-500, 501-1,000, 1,001-1500, 1501-2,000, and >2,000 cells/μl of blood, respectively. Differences in the estimated mean CD4 count between different age groups varied significantly (P=0.010). In this study, significantly higher CD4 T lymphocyte values were observed among the study population in comparison to the NRVs, and consequently we advise careful interpretation and use of extrapolated CD4 T lymphocyte values in the management of persons with diverse geographical background or health conditions.

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Fighting Viral Infections and Virus-Driven Tumors with Cytotoxic CD4+ T Cells

Cited by 32 publications

References 228 publications

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity

Activated‐cytotoxic TCRαβ+CD4+ peripheral T‐cell lymphoma with hypodermal localization: Case report of a lymphoproliferative disorder probably evolved from the CD4+ cytotoxic T‐cell subpopulation

Assessment of CD4 T Lymphocyte Cell Levels among Hepatitis B, C and E Viruses Negative Individuals in Ibadan, southwestern Nigeria

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