Tumor-infiltrating lymphocytes contain higher numbers of type 1 cytokine expressors and DR+ T cells compared with lymphocytes from tumor draining lymph nodes and peripheral blood in patients with cancer of the uterine cervix.
OBJECTIVE
The aim of this study was to compare the phenotype and function of lymphocytes collected from the peripheral blood (PBL), tumor draining regional lymph nodes (LND), and infiltrating tumor tissues (TIL) of patients with stage IB-IIA cervical cancer.


METHODS
Leukocytes from peripheral blood (n = 35), tumor draining lymph nodes (n = 33), and tumor tissues (n = 15) of cervical cancer patients were evaluated for the relative proportions of lymphocyte subsets including CD3+, CD4+, CD8+, CD19+, CD56, and the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells, as well as the ability to synthesize type 1 cytokines (IFN-gamma and IL-2) and a type 2 cytokine (IL-4) by flow cytometry.


RESULTS
In all patients, T cells (CD3+) were the major leukocyte population detected in each tissue, with CD4+ T cells being dominant in PBL and LND, while CD8+ T cells predominated in TIL (CD4:CD8 ratios, 2.4 vs 4.0 vs 0.7, respectively). CD19+ lymphocytes (B cells) were significantly higher in LND compared to PBL and TIL (P > 0.01) while CD56+ lymphocytes were higher in PBL compared to LND (P > 0.01) and TIL (P > 0.05). The early activation marker CD25 was significantly up-regulated in LND, while TIL had a higher proportion of T cells expressing the late activation marker HLA-DR. Type 1 cytokines were the dominant type produced by in vitro stimulated T cells for each population, with a greater proportion of IFN-gamma+ CD4+ and CD8+ T cells (i.e., Th1 and Tc1) and IL-2+ CD8+ T cells (Tc1) seen in TIL, as compared with LND and PBL (P > 0.01). Low percentages of IL-4+ T cells (i.e., Th2 and Tc2) were detected only in PBL.


CONCLUSIONS
This study demonstrates significant differences in the phenotype and activation state of lymphocyte subsets from different anatomical sites, as well as differences in their ability to synthesize immunostimulatory cytokines. The recruitment and accumulation of high concentrations of antigen-experienced T lymphocytes in the cervical tumor tissue may represent an important local barrier to neoplastic dissemination.
Santin
A D
AD
Department of Obstetrics and Gynecology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205-7199, USA.
Ravaggi
A
A
Bellone
S
S
Pecorelli
S
S
Cannon
M
M
Parham
G P
GP
Hermonat
P L
PL
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism; D000328:Adult; D000368:Aged; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D005260:Female; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D007376:Interleukin-2 / Q000096:biosynthesis / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis / Q000097:blood; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D008214:Lymphocytes / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000097:blood / Q000276:immunology* / Q000378:metabolism
D016207:Cytokines; D006684:HLA-DR Antigens; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D015847:Interleukin-4; D007371:Interferon-gamma