Metastatic tumour cells favour the generation of a tolerogenic milieu in tumour draining lymph node in patients with early cervical cancer.
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.
Battaglia
Alessandra
A
Gynecologic Oncology Unit, Catholic University of Rome, Rome, Italy. abattaglia@rm.unicatt.it
Buzzonetti
Alexia
A
Baranello
Cinzia
C
Ferrandina
Gabriella
G
Martinelli
Enrica
E
Fanfani
Francesco
F
Scambia
Giovanni
G
Fattorossi
Andrea
A
D000230:Adenocarcinoma / Q000276:immunology* / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018196:Carcinoma, Adenosquamous / Q000276:immunology* / Q000556:secondary; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000556:secondary; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007124:Immunoenzyme Techniques; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000276:immunology* / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D039942:Neuropilin-1 / Q000378:metabolism; D009930:Organic Chemicals; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000276:immunology* / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D009930:Organic Chemicals; C029248:Tolerogen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1