Immunosuppressive profile of a murine lung adenocarcinoma is reversed by Indomethacin

BLIDNER, A; SALATINO M; KARAS, RA; JASNIS MA; RABINOVICH GA.; DIAMENT M; KLEIN SM

Vina del Mar Chile

Congreso; ALAI 2009- Latinoamerican Congress of Immunology, 2009; 2009

Tumor–induced immune suppression is widespread in patients and experimental animals with malignant tumors and is likely to be a significant impediment to immunotherapy. Multiple mechanisms are thought to facilitate this suppression, being Myeloid Derived Suppressor Cells (MDSC) and T regulatory cells (Treg) major contributors. Our aim was to analyze immune parameters indicative of immune suppression in BALB/C mice bearing LP07 (COX+) lung tumor (TBM) during tumor growth and the effect of Indomethacin, an unspecific COX inhibitor, on these parameters. We determined 1) the effect of indo on LP07 tumor growth. 2) the content of MDSC and Treg in lymphoid organs (Spleen, tumor draining lymph nodes-TDLN-) and in the tumor at different times by FACS; 2) arginase activity in lung, spleen, liver and tumor measured as ug Urea/mg protein; 3) specific DTH response with formalinized LP07 cells by the foot pad swelling assay. Results: Indo treatment significantly inhibited tumor growth (control vs indo mm2). The percentage of MDSC (CD11b+ Gr1+) augmented significantly in the spleen of TBM in advanced stages of tumor progression (33 days) (Normal: 2,57; TBM 10 days: 2,375; TBM 20 days: 5,6; TBM 33 days :8,33, p<0,05 vs Normal), this induction was prevented with Indo treatment (4,6%). Intratumoral and TDLN CD4+CD25+Foxp3+ Tregs frequency significantly augmented during tumor growth, peaking at day 20. Interestingly Indo treatment decreased Tregs induction (p<0.05) in TDLN. Arginase activity increased in all analyzed tissues of TBM compared to normal mice. Specific DTH response decreased in late stages of tumor progression, while Indo treatment reversed this inhibition (TBM:0,06 ± 0,045; Indo:0,14 ± 0,038). Conclusion: In our model, the increment in MDSC and Tregs frequency during tumor progression correlates with specific immunosuppression shown by DTH and increased arginase activity. We suggest that Indo treatment prevented this immunosuppression by modulating COX activity in the tumor microenvironment, which is known to activate MDSC and differentiate Tregs.