TYPE I IFNS SIGNALS ON HOST CELLS MODIFY THE PATTERN OF TREG INFILTRATION IN B16 MELANOMA TUMORS

P. ARAYA, D. A. NOCERA, E. ROSELLI, G. GATTI, N. G. NUÑEZ, M. MACCIONI

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Inmunología; 2014

Sociedad Argentina de inmunologia

Early induction of type I IFNs is crucial in priming the antitumor immune response and in controlling tumor growth. Type I IFN signals through its receptor IFNAR, present in several cell types. In contrast, Tregs can compromise an effective antitumor immune response when recruited to the tumor site. In this work, we investigate whether the levels of type I IFN (generated either spontaneously or upon therapeutically treating tumor-bearing animals with Poly AU (pAU), a TLR3 ligand) can modulate the biology of Tregs in the tumor microenvironment. B16 melanoma cells generated larger tumors in ifnar--/- than in C57BL/6 (wt) mice (p≤0.05), which were infiltrated with reduced numbers of CD45+cells per gram of tumor (ifnar--/-: 1.08 x 106/gr vs wt: 6.4 x 10 6/gr, p≤0.05). However, a higher frequency of CD4+ T cells and a lower percentage of CD4+CD25+ Foxp3+ T cells were found among CD45+ cells in tumors developed in ifnar-/- mice compared to those grown in wt mice (CD4+: 35% vs 19%; CD4+CD25+ Foxp3+: 0.8% vs 8.75% respectively). When draining (DLN) and non- draining lymph nodes (NDLN) were evaluated in both strains of mice, smaller LN were observed in ifnar--/- mice (p≤0.05), but strikingly, a 4-fold increase in the number of CD45+cells were present in ifnar--/- DLN and NDLN. Interestingly, whereas the frequency of CD4+T cells did not differ between LN in both strains, the percentage of CD4+CD25+ Foxp3+ T cells among the total CD45+ population was higher in ifnar--/- LN , mainly in DLN (ifnar--/- :3.39% vs wt: 1.92%.in DLN), Intratumoral treatment with pAU, inhibited tumor growth and increased mice survival in wt mice but not in IFNAR1-/- . Lower numbers of CD4+CD25+ Foxp3+T cells were found in pAU treated tumors compared with non-treated ones; evenmore, these Foxp3+ cells expressed two fold-decreased levels of LAP1, a marker associated with TGFβ production. A decreased expression of CCL22 and CCL17 mRNA was found in pAU treated tumors. Thus, type I IFN signals on host cells modify the pattern of Treg infiltration in B16 melanoma tumors.