Suppression of tumour-specific CD4⁺ T cells by regulatory T cells is associated with progression of human colorectal cancer.
BACKGROUND
There is indirect evidence that T cell responses can control the metastatic spread of colorectal cancer (CRC). However, an enrichment of CD4(+)Foxp3(+) regulatory T cells (Tregs) has also been documented.


OBJECTIVE
To evaluate whether CRC promotes Treg activity and how this influences anti-tumour immune responses and disease progression.


METHODS
A longitudinal study of Treg activity on a cohort of patients was performed before and after tumour resection. Specific CD4(+) T cell responses were also measured to the tumour associated antigens carcinoembryonic antigen (CEA) and 5T4.


RESULTS
Tregs from 62 preoperative CRC patients expressed a highly significant increase in levels of Foxp3 compared to healthy age-matched controls (p=0.007), which returned to normal after surgery (p=0.0075). CD4(+) T cell responses to one or both of the tumour associated antigens, CEA and 5T4, were observed in approximately two-thirds of patients and one third of these responses were suppressed by Tregs. Strikingly, in all patients with tumour recurrence at 12 months, significant preoperative suppression was observed of tumour-specific (p=0.003) but not control CD4(+) T cell responses.


CONCLUSIONS
These findings demonstrate that the presence of CRC drives the activity of Tregs and accompanying suppression of CD4(+) T cell responses to tumour-associated antigens. Suppression is associated with recurrence of tumour at 12 months, implying that Tregs contribute to disease progression. These findings offer a rationale for the manipulation of Tregs for therapeutic intervention.
Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff, UK.
Gareth
G
Betts
Emma
E
Jones
Syed
S
Junaid
Tariq
T
El-Shanawany
Martin
M
Scurr
Paul
P
Mizen
Mayur
M
Kumar
Sion
S
Jones
Brian
B
Rees
Geraint
G
Williams
Awen
A
Gallimore
Andrew
A
Godkin
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003082:Colectomy; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018450:Disease Progression; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006801:Humans; D007111:Immunity, Cellular; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors
D000970:Antineoplastic Agents; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors