Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients

Samid, May Abd Al; Chaudhary, Belal; Khaled, Yazan S.; Ammori, Basil J.; Elkord, Eyad

doi:10.18632/oncotarget.7334

Cited by 34 publications

(28 citation statements)

References 35 publications

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“…Miyara et al [25] suggested CD15s 1 FoxP3 high as highly suppressive T regs , because depletion of CD15s 1 CD4 1 T cells from human blood enhanced in-vitro anti-tumour and anti-viral antigen responses. Moreover, Helios has been reported previously as a vital marker for highly suppressive T regs in the activated state, which express LAP and GARP (glycoprotein A repetitions predominant) and secrete interleukin (IL)-10 [23,39]. We found LAP expression mainly in Helios 1 T reg in both HD and PBC.…”

Section: F -H -F -H + F + H + F + H -F -H -F -H + F + H + F + Hmentioning

confidence: 54%

In-vitro effect of pembrolizumab on different T regulatory cell subsets

Toor

Khaja

Alkurd

et al. 2017

Clinical and Experimental Immunology

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Programmed death-1 (PD-1) and interactions with PD-ligand 1 (PD-L1) play critical roles in the tumour evasion of immune responses through different mechanisms, including inhibition of effector T cell proliferation, reducing cytotoxic activity, induction of apoptosis in tumour-infiltrating T cells and regulatory T cell (T ) expansion. Effective blockade of immune checkpoints can therefore potentially eliminate these detrimental effects. The aim of this study was to investigate the effect of anti-PD-1 antibody, pembrolizumab, on various T subpopulations. Peripheral blood mononuclear cells (PBMC) from healthy donors (HD) and primary breast cancer patients (PBC) were treated in vitro with pembrolizumab, which effectively reduced PD-1 expression in both cohorts. We found that PD-1 was expressed mainly on CD4 CD25 T cells and pembrolizumab had a greater effect on PD-1 expression in CD4 CD25 T cells, compared to CD4 CD25 cells. In addition, pembrolizumab did not affect the expression levels of T -related markers, including cytotoxic T lymphocyte antigen-4 (CTLA-4), CD15s, latency-associated peptide (LAP) and Ki-67. Moreover, we report that CD15s is expressed mainly on forkhead box P3 (FoxP3) Helios T in HD, but it is expressed on FoxP3 Helios T subset in addition to FoxP3 Helios T in PBC. Pembrolizumab did not affect the levels of FoxP3 Helios T subsets in both cohorts. Taken together, our study suggests that pembrolizumab does not affect T or change their phenotype or function but rather blocks signalling via the PD-1/PD-L1 axis in activated T cells.

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Section: F -H -F -H + F + H + F + H -F -H -F -H + F + H + F + Hmentioning

confidence: 54%

In-vitro effect of pembrolizumab on different T regulatory cell subsets

Toor

Khaja

Alkurd

et al. 2017

Clinical and Experimental Immunology

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“…The numbers of Foxp3 + T cells were found to be increased in immune cells infiltrating pancreatic cancers and in draining lymph nodes (7,22), however, the mechanism by which Foxp3+Treg populations are expanded in peripheral blood from the tumor environment remained unclear (23). The mechanism of Foxp3 + Treg induction in the tumor microenvironment was linked to the enzyme indoleamine-2, 3-deoxygenase (IDO).…”

Section: Discussionmentioning

confidence: 99%

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

Ikemoto

Shimada

Ishikawa

et al. 2017

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Abstract. Background Foxp3 + regulatory T cells (Foxp3 + Tregs) play an important role in tumor immunity (1-3). Populations of peripheral Foxp3 + Tregs were found to be greater in pancreatic cancer patients than in healthy controls, with peripheral Foxp3 + Treg populations strongly correlating with TMN classifications (4). In addition, peripheral Foxp3 + Treg populations were found to significantly correlate with the pathological aggressiveness of intraductal papillary mucinous neoplasms (IPMNs), a correlation dependent on Notch signaling (5). Although Treg populations have been reported to be higher in peritumoral lesions and in draining lymph nodes, the precise mechanism underlying the increase in peripheral Tregs in cancer patients has not been determined (6, 7).Treg expansion following organ transplantation has been reported to depend on indoleamine 2, 3-dioxygenase (IDO) activity of dendritic cells (DCs) (8). IDO is a critical enzyme for maintaining pregnancy (9) and plays an important role in tumor immunity (10,11). An investigation of the associations of IDO with IPMN aggressiveness and Treg immunity showed that Treg increases induced by IDO + DCs are associated with peritumoral lesions (12). However, the mechanism underlying the expansion of Tregs in peripheral blood, as well as in the peritumoral environment, remains unclear. Tregs are easily influenced by other factors that alter host immunology, such as infection and chemo/radiation therapy, suggesting the need for more precise and stable immunological parameters to evaluate tumor immunity, especially after surgery.CD4 + CD49b + LAG3 + regulatory T cells (type 1 regulatory T cells, or Tr1s) were recently reported to have strong regulatory activities in autoimmune diseases (13). Tr1s were originally found in the peripheral blood of patients with severe combined immunodeficiency and long-term mixed chimerism after human leukocyte antigen (HLA)-mismatched fetal liver hematopoietic stem cell transplantation (14). The primary 5541

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“…Although a subset of T-cells expressed Foxp3 at culture's end (Supplemental Figure S3), this subset was almost completely lacking co-expression of latency-associated peptide (LAP) and/or glycoprotein A repetitions predominant LRRC32 (GARP) (Supplemental Figure S4), a composite phenotype associated with activated effector T-cells rather than with Treg function [52–54]. A parallel absence of LAP and/or GARP expression was also observed for Helios+ T-cells (Supplemental Figure S4), indicating that they too were not Tregs [53, 54]. Finally, as expected, subsets of both CD4+ and CD8+ T-cells displayed physiologic checkpoint receptors for B7.1 (CTLA4) and/or for PD-L1 (PD-1) (Supplemental Figure S3 [55, 56]).…”

Section: Resultsmentioning

confidence: 99%

Surrogatein vitroactivation of innate immunity synergizes with interleukin-7 to unleash rapid antigen-driven outgrowth of CD4+ and CD8+ human peripheral blood T-cells naturally recognizing MUC1, HER2/neu and other tumor-associated antigens

et al. 2016

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Effective adoptive immunotherapy has proved elusive for many types of human cancer, often due to difficulties achieving robust expansion of natural tumor-specific T-cells from peripheral blood. We hypothesized that antigen-driven T-cell expansion might best be triggered in vitro by acute activation of innate immunity to mimic a life-threatening infection. Unfractionated peripheral blood mononuclear cells (PBMC) were subjected to a two-step culture, first synchronizing their exposure to exogenous antigens with aggressive surrogate activation of innate immunity, followed by ?-chain cytokine-modulated T-cell hyperexpansion. Step 1 exposure to GM-CSF plus paired Toll-like receptor agonists (resiquimod and LPS), stimulated abundant IL-12 and IL-23 secretion, as well as upregulated co-stimulatory molecules and CD11c expression within the myeloid (CD33+) subpopulation. Added synthetic long peptides (>20aa) derived from widely expressed oncoproteins (MUC1, HER2/neu and CMVpp65), were reliably presented to CD4+ T-cells and cross-presented to CD8+ T-cells. Both presentation and cross-presentation demonstrated proteasomal and Sec61 dependence that could bypass the endoplasmic reticulum. Step 2 exposure to exogenous IL-7 or IL-7+IL-2 produced selective and sustained expansion of both CD4+ and CD8+ peptide-specific T-cells with a predominant interferon-?-producing T1-type, as well as the antigen-specific ability to lyse tumor targets. Other ?-chain cytokines and/or combinations were initially proliferogenic, but followed by a contractile phase not observed with IL-7 or IL-7+IL-2. Regulatory T-cells were minimally propagated under these culture conditions. This mechanistically rational culture sequence, effective even for unvaccinated donors, enables rapid preparation of T-cells recognizing tumor-associated antigens expressed by the majority of human cancers, including pancreatic cancers, breast cancers and glioblastomas.

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Combining FoxP3 and Helios with GARP/LAP markers can identify expanded Treg subsets in cancer patients

Cited by 34 publications

References 35 publications

In-vitro effect of pembrolizumab on different T regulatory cell subsets

In-vitro effect of pembrolizumab on different T regulatory cell subsets

Peripheral Tr1 and Foxp3+ Treg as Markers of Recurrent Malignancies in Patients with Hepato-Biliary Pancreatic Cancers

Surrogatein vitroactivation of innate immunity synergizes with interleukin-7 to unleash rapid antigen-driven outgrowth of CD4+ and CD8+ human peripheral blood T-cells naturally recognizing MUC1, HER2/neu and other tumor-associated antigens

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