Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer

Alessandra Battaglia, Alexia Buzzonetti, Cinzia Baranello, Gabriella Ferrandina, Enrica Martinelli, Francesco Fanfani, Giovanni Scambia, Andrea Fattorossi

Research output: Contribution to journalArticle

Abstract

Objective: We compared the immune system state in metastatic tumour draining lymph nodes (mTDLN) and metastasis free TDLN (mfTDLN) in 53 early stage cervical cancer patients to assess whether the presence of metastatic tumour cells worsen the balance between an efficacious anti-tumour and a tolerogenic microenvironment. Methods: The immune system state was measured by immunophenotypic and functional assessment of suppressor and effector immune cell subsets. Results: Compared to mfTDLN, mTDLN were significantly enriched in CD4+Foxp3+ regulatory T cells (Treg), which, in addition, exhibited an activated phenotype (HLA-DR+ and CD69+). Treg in mTDLN were also significantly enriched in neuropilin-1 (Nrp1) expressing cells, a subset particularly potent in dampening T cell responses. mTDLN tended to be enriched in a population of CD8+Foxp3+T cells (operationally defined as CD8+Treg) that showed a suppressor potency similar to Treg under the same experimental conditions. Plasmacytoid dendritic cells (pDC) and myeloid DC (mDC) generally show distinct roles in inducing T cell tolerance and activation, respectively. In line with the excess of suppressor T cells, the ratio pDC to mDC was significantly increased in mTDLN. Immunohistochemical testing showed that metastatic tumour cells produced the vascular endothelial growth factor, a natural ligand for Nrp1 expressed on the cell surface of Nrp1+Treg and pDC, and therefore a potential mediator by which tumour cells foster immune privilege in mTDLN. Consistent with the overall tolerogenic profile, mTDLN showed a significant Tc2 polarisation and tended to contain lower numbers of CD45RA+CD27- effector memory CD8+T cells. Conclusions: The increased recruitment of suppressor type cells concomitant with the scarcity of cytotoxic type cells suggests that in mTDLN the presence of tumour cells could tip the balance against anti-tumour immune response facilitating the survival of metastatic tumour cells and possibly contributing to systemic tolerance.

Original languageEnglish
Pages (from-to)1363-1373
Number of pages11
JournalCancer Immunology, Immunotherapy
Volume58
Issue number9
DOIs
Publication statusPublished - Sep 2009

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Uterine Cervical Neoplasms
Lymph Nodes
Neoplasms
Neuropilin-1
T-Lymphocytes
Dendritic Cells
Immune System
Neoplasm Metastasis
HLA-DR Antigens
Regulatory T-Lymphocytes
Vascular Endothelial Growth Factor A

Keywords

  • Cervical cancer
  • Immune state
  • Regulatory CD8Foxp3 cells
  • Regulatory T cells
  • Tumour draining lymph nodes
  • Tumour metastasis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer. / Battaglia, Alessandra; Buzzonetti, Alexia; Baranello, Cinzia; Ferrandina, Gabriella; Martinelli, Enrica; Fanfani, Francesco; Scambia, Giovanni; Fattorossi, Andrea.

In: Cancer Immunology, Immunotherapy, Vol. 58, No. 9, 09.2009, p. 1363-1373.

Research output: Contribution to journalArticle

Battaglia, A, Buzzonetti, A, Baranello, C, Ferrandina, G, Martinelli, E, Fanfani, F, Scambia, G & Fattorossi, A 2009, 'Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer', Cancer Immunology, Immunotherapy, vol. 58, no. 9, pp. 1363-1373. https://doi.org/10.1007/s00262-008-0646-7
Battaglia, Alessandra ; Buzzonetti, Alexia ; Baranello, Cinzia ; Ferrandina, Gabriella ; Martinelli, Enrica ; Fanfani, Francesco ; Scambia, Giovanni ; Fattorossi, Andrea. / Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer. In: Cancer Immunology, Immunotherapy. 2009 ; Vol. 58, No. 9. pp. 1363-1373.
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AU - Buzzonetti, Alexia

AU - Baranello, Cinzia

AU - Ferrandina, Gabriella

AU - Martinelli, Enrica

AU - Fanfani, Francesco

AU - Scambia, Giovanni

AU - Fattorossi, Andrea

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N2 - Objective: We compared the immune system state in metastatic tumour draining lymph nodes (mTDLN) and metastasis free TDLN (mfTDLN) in 53 early stage cervical cancer patients to assess whether the presence of metastatic tumour cells worsen the balance between an efficacious anti-tumour and a tolerogenic microenvironment. Methods: The immune system state was measured by immunophenotypic and functional assessment of suppressor and effector immune cell subsets. Results: Compared to mfTDLN, mTDLN were significantly enriched in CD4+Foxp3+ regulatory T cells (Treg), which, in addition, exhibited an activated phenotype (HLA-DR+ and CD69+). Treg in mTDLN were also significantly enriched in neuropilin-1 (Nrp1) expressing cells, a subset particularly potent in dampening T cell responses. mTDLN tended to be enriched in a population of CD8+Foxp3+T cells (operationally defined as CD8+Treg) that showed a suppressor potency similar to Treg under the same experimental conditions. Plasmacytoid dendritic cells (pDC) and myeloid DC (mDC) generally show distinct roles in inducing T cell tolerance and activation, respectively. In line with the excess of suppressor T cells, the ratio pDC to mDC was significantly increased in mTDLN. Immunohistochemical testing showed that metastatic tumour cells produced the vascular endothelial growth factor, a natural ligand for Nrp1 expressed on the cell surface of Nrp1+Treg and pDC, and therefore a potential mediator by which tumour cells foster immune privilege in mTDLN. Consistent with the overall tolerogenic profile, mTDLN showed a significant Tc2 polarisation and tended to contain lower numbers of CD45RA+CD27- effector memory CD8+T cells. Conclusions: The increased recruitment of suppressor type cells concomitant with the scarcity of cytotoxic type cells suggests that in mTDLN the presence of tumour cells could tip the balance against anti-tumour immune response facilitating the survival of metastatic tumour cells and possibly contributing to systemic tolerance.

AB - Objective: We compared the immune system state in metastatic tumour draining lymph nodes (mTDLN) and metastasis free TDLN (mfTDLN) in 53 early stage cervical cancer patients to assess whether the presence of metastatic tumour cells worsen the balance between an efficacious anti-tumour and a tolerogenic microenvironment. Methods: The immune system state was measured by immunophenotypic and functional assessment of suppressor and effector immune cell subsets. Results: Compared to mfTDLN, mTDLN were significantly enriched in CD4+Foxp3+ regulatory T cells (Treg), which, in addition, exhibited an activated phenotype (HLA-DR+ and CD69+). Treg in mTDLN were also significantly enriched in neuropilin-1 (Nrp1) expressing cells, a subset particularly potent in dampening T cell responses. mTDLN tended to be enriched in a population of CD8+Foxp3+T cells (operationally defined as CD8+Treg) that showed a suppressor potency similar to Treg under the same experimental conditions. Plasmacytoid dendritic cells (pDC) and myeloid DC (mDC) generally show distinct roles in inducing T cell tolerance and activation, respectively. In line with the excess of suppressor T cells, the ratio pDC to mDC was significantly increased in mTDLN. Immunohistochemical testing showed that metastatic tumour cells produced the vascular endothelial growth factor, a natural ligand for Nrp1 expressed on the cell surface of Nrp1+Treg and pDC, and therefore a potential mediator by which tumour cells foster immune privilege in mTDLN. Consistent with the overall tolerogenic profile, mTDLN showed a significant Tc2 polarisation and tended to contain lower numbers of CD45RA+CD27- effector memory CD8+T cells. Conclusions: The increased recruitment of suppressor type cells concomitant with the scarcity of cytotoxic type cells suggests that in mTDLN the presence of tumour cells could tip the balance against anti-tumour immune response facilitating the survival of metastatic tumour cells and possibly contributing to systemic tolerance.

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