A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

Shah, Walayat; Yan, Xiaofei; Li, Jing; Zhou, Yi; Chen, Hongwei; Wang, Yili

doi:10.1038/cmi.2010.56

Cited by 222 publications

(178 citation statements)

References 51 publications

(56 reference statements)

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“…Thus, the development of an immune response mediated by CD4 ϩ Th1 lymphocytes has been associated with regression of ano-genital warts (21). In addition, the increased frequency of cervical cancer in patients with altered CD4 ϩ cells highlights the importance of this cell population in the control of HPV infection (23).…”

Section: Discussionmentioning

confidence: 99%

Human Papillomavirus Immunization Is Associated with Increased Expression of Different Innate Immune Regulatory Receptors

Colmenares

Noyola

Monsiváis‐Urenda

et al. 2012

Clin. Vaccine Immunol.

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ABSTRACTHuman papillomavirus (HPV) is able to inhibit the secretion of gamma interferon (IFN-γ) and the expression of some immune innate cell receptors. Immunoglobulin-like transcript 2 (ILT2) is a regulatory receptor that seems to participate in the pathogenesis of viral infections. We have studied the expression and function of ILT2 and the expression of other NK cell receptors in 23 healthy women before and after immunization with the quadrivalent HPV (type 6/11/16/18) vaccine (Gardasil). Receptor expression was analyzed by flow cytometry in freshly isolated peripheral blood mononuclear cells as well as afterin vitrostimulation with the quadrivalent HPV (type 6/11/16/18) vaccine. In addition, the regulatory function of ILT2 on cell proliferation and IFN-γ production was analyzed. We found a significant increase in the expression of ILT2 by NK and CD3+CD56+lymphocytes and monocytes after quadrivalent HPV (type 6/11/16/18) vaccine immunization. In addition, thein vitrostimulation with the quadrivalent HPV (type 6/11/16/18) vaccine also increased the proportion of CD3−CD56+ILT2+NK cells. Although the inhibitory function of ILT2 on cell proliferation was enhanced after HPV immunization, thein vitroengagement of this receptor did not affect the synthesis of IFN-γ induced by HPV. Finally, a significant increase in the expression of NKG2D, NKp30, and NKp46 by NK and CD3+CD56+lymphocytes was detected after quadrivalent HPV (type 6/11/16/18) vaccine immunization. Our data indicate that HPV immunization is associated with significant changes in the expression and function of different innate immune receptors, including ILT2, which may participate in the protective effect of HPV vaccines.

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Section: Discussionmentioning

confidence: 99%

Human Papillomavirus Immunization Is Associated with Increased Expression of Different Innate Immune Regulatory Receptors

Colmenares

Noyola

Monsiváis‐Urenda

et al. 2012

Clin. Vaccine Immunol.

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“…Shah and colleagues used 2-color IHC to identify both CD4þFoxP3þ and CD8þFoxP3þ T cells in cervical cancer. Intriguingly, they found CD8þFoxP3þ T cells at a mean number of 3.32 per high-power field and CD4þFoxP3þ T cells at a mean number of 11.45 per high-power field (30). Thus, had they used FoxP3 as a single marker, only $75% of the cells they measured would have been CD4þ T cells, which underscores the fact that not all FoxP3þ T cells are conventional Tregs.…”

Section: Use Of Multiple Markers To Define Foxp3þ T Cellsmentioning

confidence: 97%

“…In the end, we reviewed 58 studies encompassing 16 different cancer types (Table 1), including bladder (19), breast (21)(22)(23)(24)(25)(26)(27)(28), cervical (29,30), colorectal (12,(31)(32)(33)(34)(35)(36)(37)(38)(39), endometrial (40)(41)(42), gastric (14,(43)(44)(45)(46), head and neck (47), hepatocellular (48)(49)(50)(51)(52), lung (53,54), melanoma (55)(56)(57)(58), mesothelial (59), oral (4,(60)(61)(62)(63), ovarian (2,3,…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the Literature

deLeeuw

Kost

Kakal

et al. 2012

Clinical Cancer Research

394

307

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CD8þ tumor-infiltrating lymphocytes (TIL) are associated with survival in a variety of cancers. A second subpopulation of TIL, defined by forkhead box protein P3 (FoxP3) expression, has been reported to inhibit tumor immunity, resulting in decreased patient survival. On the basis of this premise, several groups are attempting to deplete FoxP3þ T cells to enhance tumor immunity. However, recent studies have challenged this paradigm by showing that FoxP3þ T cells exhibit heterogeneous phenotypes and, in some cohorts, are associated with favorable prognosis. These discrepant results could arise from differences in study methodologies or the biologic properties of specific cancer types. Here, we conduct the first systematic review of the prognostic significance of FoxP3þ T cells across nonlymphoid cancers (58 studies from 16 cancers). We assessed antibody specificity, cell-scoring strategy, multivariate modeling, use of single compared with multiple markers, and tumor site. Two factors proved important. First, when FoxP3 was combined with one additional marker, double-positive T cells were generally associated with poor prognosis. Second, tumor site had a major influence. FoxP3þ T cells were associated with poor prognosis in hepatocellular cancer and generally good prognosis in colorectal cancer, whereas other cancer types were inconsistent or understudied. We conclude that FoxP3þ T cells have heterogeneous properties that can be discerned by the use of additional markers. Furthermore, the net biologic effects of FoxP3þ T cells seem to depend on the tumor site, perhaps reflecting microenvironmental differences. Thus, depletion of FoxP3þ T cells might enhance tumor immunity in some patient groups but be detrimental in others.

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“…9 These observations suggest that the success of immunotherapy for cancer may ultimately depend on the balance between Treg and Teff cells. 10,11 Increasing evidence indicates that Tregs mediate immunosuppressive functions through the utilization of many soluble mediators and cell-to-cell contact, further inducing a positive feedback loop. 1 Bopp et al 12 showed that natural Tregs can transfer cyclic adenosine monophosphate (cAMP) to Teff cells, resulting in increased intracellular cAMP concentrations in Teff cells.…”

Section: Introductionmentioning

confidence: 99%

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Dou

Liu

et al. 2012

Cell Mol Immunol

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Lymphoma cells mobilize many mechanisms to evade the immune system. There is substantial evidence that CD4 1 CD25 1 regulatory T cells (Tregs) play a key role in the control of immune evasion. Tregs can transfer cyclic adenosine monophosphate (cAMP) to effector T cells, suggesting an association between Tregs' immune-evasion role and the intracellular cAMP pathway. In this study, we used A20 B-cell lymphoma mice as aggressive tumor models to investigate the mechanism of the depletion of Tregs by low-dose cyclophosphamide (CY, 20 mg/kg). The tumor-bearing mice had longer survival times and slower tumor growth rates following treatment with CY, but its effects were temporary. Along with the depletion of Tregs by low-dose CY treatment, the expression of interleukin-2 (IL-2) in T effector cells increased, and intracellular cAMP concentrations in immune cells decreased. Our study demonstrates the ability of low-dose CY to reverse Tregs-mediated immune evasion in a mouse model. The changes in intracellular cAMP concentrations correlated with the upregulation of effector T cells and the downregulation of Tregs, indicating the close association of cAMP analogs and low-dose CY in the immune therapy of B-cell lymphoma.

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A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4+FOXP3+ regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervix

Cited by 222 publications

References 51 publications

Human Papillomavirus Immunization Is Associated with Increased Expression of Different Innate Immune Regulatory Receptors

Human Papillomavirus Immunization Is Associated with Increased Expression of Different Innate Immune Regulatory Receptors

The Prognostic Value of FoxP3+ Tumor-Infiltrating Lymphocytes in Cancer: A Critical Review of the Literature

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

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