Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner.
OBJECTIVE
Naturally occurring regulatory T (T(R)) cells suppress autoreactive T cells whereas adaptive T(R) cells, induced in the periphery, play an important role in chronic viral diseases and cancer. Several studies indicate that cyclooxygenase (COX) inhibitors prevent cancer development of colon adenomas and delay disease progression in patients with colorectal cancer (CRC). We have shown that adaptive T(R) cells express COX-2 and produce PGE(2) that suppress effector T cells in a manner that is reversed by COX-inhibitors.


RESULTS
Here we demonstrate that CRC patients have elevated levels of PGE(2) in peripheral blood, and CRC tissue samples and draining lymph nodes display increased numbers of FOXP3+ T(R) cells. Depletion of T(R) cells from PBMC enhanced anti-tumor T-cell responses to peptides from carcinoembryonic antigen. Furthermore, the COX inhibitor indomethacin and the PKA type I antagonist Rp-8-Br-cAMPS significantly improved the anti-tumor immune activity.


CONCLUSIONS
We suggest that adaptive T(R) cells contribute to an immunosuppressive microenvironment in CRC and inhibit effector T cells by a COX-2-PGE(2)-dependent mechanism and thereby facilitate tumor growth. Therapeutic strategies targeting T(R) cells and the PGE(2)-cAMP pathway may be interesting to pursue to enhance anti-tumor immune activity in CRC patients.
Yaqub
Sheraz
S
The Biotechnology Centre of Oslo, University of Oslo, P.O. Box 1112, Blindern 0317 Oslo, Norway.
Henjum
Karen
K
Mahic
Milada
M
Jahnsen
Frode L
FL
Aandahl
Einar M
EM
Bjørnbeth
Bjørn A
BA
Taskén
Kjetil
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology
D000970:Antineoplastic Agents; D051546:Cyclooxygenase 2; D015232:Dinoprostone