Tumor‐infiltrating CD14‐positive myeloid cells and CD8‐positive T‐cells prolong survival in patients with cervical carcinoma

Steenwijk, Peggy J. de Vos van; Ramwadhdoebé, Tamara H.; Goedemans, Renske; Doorduijn, Elien M.; Ham, Jannemieke; Gorter, Arko; Hall, Thorbald van; Kuijjer, Marieke L.; Poelgeest, Mariëtte I.E. van; Burg, Sjoerd H. van der; Jordanova, Ekaterina S.

doi:10.1002/ijc.28309

Cited by 115 publications

(113 citation statements)

References 49 publications

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“…Deciphering the exact molecular cues responsible for macrophage polarization during treatment seems critical for effective therapy. Recently, we have demonstrated a positive correlation of a dense infiltration of M1-type macrophages with patient survival in a cohort of cervical cancer patients (45), supporting the notion that macrophage skewing toward antitumor activity, rather than macrophage depletion, might be the optimal strategy. Our study illustrates that immunogenic cancer vaccines can be instrumental to induce such a repolarization of intratumoral macrophages.…”

Section: Discussionsupporting

confidence: 55%

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Sluis

Sluijter

Duikeren

et al. 2015

Cancer Immunology Research

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Abundant macrophage infiltration of solid cancers commonly correlates with poor prognosis. Tumor-promoting functions of macrophages include angiogenesis, metastasis formation, and suppression of Th1-type immune responses. Here, we show that successful treatment of cervical carcinoma in mouse models with synthetic long peptide (SLP) vaccines induced influx of cytokineproducing CD8 T cells that strongly altered the numbers and phenotype of intratumoral macrophages. On the basis of the expression of CD11b, CD11c, F4/80, Ly6C, Ly6G, and MHC II, we identified four myeloid subpopulations that increased in numbers from 2.0-fold to 8.7-fold in regressing tumors. These changes of the intratumoral myeloid composition coincided with macrophage recruitment by chemokines, including CCL2 and CCL5, and were completely dependent on a vaccine-induced influx of tumor-specific CD8 T cells. CD4 T cells were dispensable. Incubation of tumor cells with T cell-derived IFNg and TNFa recapitulated the chemokine profile observed in vivo, confirming the capacity of antitumor CD8 T cells to mediate macrophage infiltration of tumors. Strikingly, complete regressions of large established tumors depended on the tumor-infiltrating macrophages that were induced by this immunotherapy, because a smallmolecule drug inhibitor targeting CSF-1R diminished the number of intratumoral macrophages and abrogated the complete remissions. Survival rates after therapeutic SLP vaccination deteriorated in the presence of CSF-1R blockers. Together, these results show that therapeutic peptide vaccination could induce cytokine-producing T cells with strong macrophage-skewing capacity necessary for tumor shrinkage, and suggest that the development of macrophage-polarizing, rather than macrophage-depleting, agents is warranted.

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Section: Discussionsupporting

confidence: 55%

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Sluis

Sluijter

Duikeren

et al. 2015

Cancer Immunology Research

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“…Tumors with high IL-6 expression displayed a dense infiltration with CD14CCD33¡CD163C cells and CD14CCD33¡CD163C cells, specifically the mature (CD33-) type of myeloid cells. Our observation that the expression of IL-6 was correlated with the presence of CD14CCD33¡CD163-cells, potentially reflecting recent infiltrated monocytes or M1 macrophages, 24 is somewhat counterintuitive. However, as the number of these tumor-infiltrating cells was generally low when compared to other cancer types, 24 and is directly correlated to co-infiltration with much larger quantities of suppressive CD33¡CD163C cells, this association is more likely to reflect that in essence IL-6 expressing tumors induce a hostile tumor immune environment.…”

Section: Discussioncontrasting

confidence: 60%

Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

et al. 2014

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y These authors contributed equally to this study.Keywords: epithelial ovarian cancer, IL-6, interleukin-6; IL-6R, interleukin-6 receptor, pSTAT3, tumor-infiltrating myeloid cells Abbreviations: DSS, disease-specific survival; EOC, epithelial ovarian cancer; IL-6R, interleukin-6, IL-6, interleukin-6 receptor; FIGO, International Federation of Gynecology and Obstetrics; MDSC, myeloid-derived suppressor cell; pSTAT3, phosphorylated signal transducer and activator of transcription 3; T reg, regulatory T cell; TMA, tissue microarray; TAM, tumor-associated macrophage; TIL, tumor-infiltrating lymphocytes; TIM, tumor-infiltrating myeloid cellAn increased level of interleukin-6 (IL-6) in epithelial ovarian cancer (EOC) is correlated with a worse prognosis. IL-6 stimulates tumor-growth and inflammation. We investigated the intricate interaction between the IL-6 signaling pathway and tumor-infiltrating myeloid cells (TIMs) to determine their prognostic impact in EOC. 160 EOC samples were analyzed for the expression of IL-6, its receptor (IL-6R) and downstream signaling via pSTAT3 by immunohistochemistry. Triple color immunofluorescence confocal microscopy was used to identify myeloid cell populations by CD14, CD33, and CD163. The relationship between these markers, tumor-infiltrating immune cells, clinical-pathological characteristics and survival was investigated. EOC displayed a dense infiltration with myeloid cells, in particular of the CD163 C type. The distribution pattern of all myeloid subtypes was comparable among the different histological subtypes. Analysis of the tumor cells revealed a high expression of IL-6R in 15% and of IL-6 in 23% of patients. Interestingly, tumors expressing IL-6 or IL-6R formed two different groups. Tumors with a high expression of IL-6R displayed low mature myeloid cell infiltration and a longer disease-specific survival (DSS), especially in late stage tumors. High expression of IL-6R was an independent prognostic factor for survival by multivariate analyses (hazard ratio D 0.474, p D 0.011). In contrast, tumors with high epithelial IL-6 expression displayed a dense infiltration of mature myeloid cells and were correlated with a shorter DSS. Furthermore, in densely CD8 C T-cell infiltrated tumors, the ratio between these lymphoid cells and CD163 C myeloid cells was predictive for survival. Thus, IL-6 and IL-6R are opposite markers for myeloid cell infiltration and survival.

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“…20 Other studies also showed a positive relationship between M1 infiltration and survival. [36][37][38][39][40] Notably, HPV-induced vulvar carcinomas are known for their good overall prognosis and survival rate of approximately 80%.…”

Section: Discussionmentioning

confidence: 92%

“…32,33 Triple immunofluorescent confocal microscopy Simultaneous detection of monocytes was carried out by triple fluorescent staining and confocal microscopy as described previously. 20 In brief, sections were deparaffinized and antigen retrieval was performed in pre-heated Tris-EDTA buffer pH 9.0. Primary antibodies: CD14 (anti-CD14, mouse IgG2a, clone 7; Novocastra 1:50), CD33 (anti-CD33, mouse IgG2b, clone PWS44; Novocastra (1:100) and CD163 (anti-CD163, mouse IgG1, clone 10D6; Novocastra 1:1,600).…”

Section: Patient Materialsmentioning

confidence: 99%

“…Interestingly, in HPV-induced cervical cancer the intraepithelial infiltration with high numbers of M1 macrophages is an independent prognostic factor for a favorable survival. 20 The type of myeloid cells infiltrate could influence the uVIN microenvironment and as such may also influence the outcome of immunotherapeutic approaches for HPV-induced vulvar neoplasia. [5][6][7][8]21 Current knowledge of the character of uVIN infiltrating myeloid cells is limited.…”

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confidence: 99%

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Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia

Esch

Poelgeest

Trimbos

et al. 2014

Intl Journal of Cancer

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Human papilloma virus (HPV)-induced usual-type vulvar intraepithelial neoplasia (uVIN) is infiltrated by myeloid cells but the type and role of these cells is unclear. We used triple immunofluorescent confocal microscopy to locate, identify and quantify myeloid cells based on their staining pattern for CD14, CD33 and CD163 in a cohort of 43 primary and 20 recurrent uVIN lesions, 21 carcinomas and 26 normal vulvar tissues. The progressive course of uVIN is characterized by an increase in both intraepithelial and stromal mature M1 and M2 macrophages. While the M2 macrophages outnumber M1 macrophages in healthy controls and uVIN, they are matched in number by M1 macrophages in cancer. Importantly, uVIN patients with a dense intraepithelial infiltration with mature CD141 macrophages (irrespective of M1 or M2 type) displayed approximately a six times higher risk to develop a recurrence and a high number of these cells constituted an independent prognostic factor for recurrence. In addition, a dense intraepithelial CD141 cell infiltration was associated with high numbers of intraepithelial CD41 Tregs and low numbers of stromal CD81TIM31 T cells. Patients with low numbers of intraepithelial CD141 cells and high numbers of stromal CD81TIM31 cells showed the best recurrence-free survival. These data clearly show the importance of the local immune response in HPV-induced vulvar neoplasia and may be of help in predicting the prognosis of patients or their response to immunotherapy.Usual-type vulvar intraepithelial neoplasia (uVIN) lesions are caused by a persistent high-risk human papilloma virus (HPV) infection (mainly HPV 16) and are characterized by high recurrences, a low spontaneous regression rate of 1.5% and a malignant potential of 3-4% in treated patients. [1][2][3] Treatment of uVIN lesions is indispensable since 80% of patients suffer from symptoms as pruritis and pain. 2-4 Conventional treatment consistent of potential disfiguring surgical interventions is associated with psychosexual problems and is increasingly replaced by either standardized immunotherapy with imiquimod or immunotherapy in experimental setting by therapeutic vaccination or photodynamic therapy, with promising clinical successes. [2][3][4][5][6][7][8] The incidence of hrHPV-induced dysplasia is increased in immunocompromised patients highlighting the essential role of the immune system in viral clearance. 9,10 Spontaneous regression of HPV is associated with systemic HPV-specific CD41 and CD81 immune responses, however in most of the patients with uVIN these T cell responses are either weak or absent. 11,12 In addition, the local innate immune cell environment is known to influence innate and adaptive immune responses in tumors. 13,14 Monocytes are innate immune cells which can differentiate into dendritic cells (DCs) or macrophages in response to local factors. 13 DCs process and present antigens to T cells, stimulate cytotoxicity of NK cells and initiate the adaptive immune response. 15 Studies of the microenvironment in uVIN revealed that ...

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Tumor‐infiltrating CD14‐positive myeloid cells and CD8‐positive T‐cells prolong survival in patients with cervical carcinoma

Cited by 115 publications

References 49 publications

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression

Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

Intraepithelial macrophage infiltration is related to a high number of regulatory T cells and promotes a progressive course of HPV‐induced vulvar neoplasia

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