Immunosuppressive profile of a murine lung adenocarcinoma is reversed by

ADA BLIDNER; MARIANA SALATINO; ROMINA A KARAS; GABRIEL A RABINOVICH; MIRIAM J DIAMENT; SLOBODANKA M KLEIN

Viña del Mar, Chile

Congreso; 9th Latin American Congress of Immunology; 2009

Asociación Latinoamericana de Inmunología

Tumor–induced immune suppression is widespread in patients and experimental animals with malignant tumors and is a significant impediment to immunotherapy. Myeloid-Derived Suppressor Cells (MDSC) and T regulatory cells (Tregs)  contribute facilitating this suppression state. 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, a non-specific COX inhibitor. We determined 1) the effect of indo on LP07 tumor growth. 2) the content of MDSC and Treg cells in lymphoid organs (spleen, tumor-draining lymph nodes-TDLN-) and in the tumors at different times by FACS; 3) arginase activity in lung, spleen, liver and tumor measured as µg Urea/mg protein; 4) 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) (TBM33 days :8,33, p<0,05 vs control), 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 cell induction (p<0.05) in TDLN. Arginase activity increased in all analyzed tissues of TBM compared to those of control 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 demonstrated by DTH responses  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 Treg cells.