Immunotherapy based on the TLR3 ligand Poly A:U modifies the tumor-associated myeloid compartment upregulating PDL1 specifically on MHCII monocytes on a type I IFN-dependent manner

ROSELLI, E; ARAYA, P; NUÑEZ, NG; STEMPIN, CC; PIAGGIO, E; MACCIONI, M

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias. LXV Reunión Sociedad Argentina de Inmunología.; 2017

Poly A:U (pAU) is a synthetic dsRNA which signals throughTLR3 to modulate an immune response by inducing the release oftype I IFNs on a broad range of cells including cancer cells andtumour-associated myeloid populations. Relying on this, pAU canbe exploited as an immune-adjuvant on cancer therapy to improvean antitumor immune response. In this work, we evaluated the effectof pAU treatment on a murine B16 melanoma cancer modelfocusing on the myeloid compartment, including tumour-associatedmacrophages (TAMs - CD45+; CD11b+; F4/80+; LyC6-; CD24-), tumour-infiltrating DCs (CD45+; CD11b+; CD24+; CD11c+; MHCII+), togetherwith tumour-associated monocytes (CD45+; CD11b+; Ly6C+;CCR2+) which can be divided into MHCII+ and MHCII- monocytes.We demonstrated that a three-dose regime of intratumoral treatmentwith pAU (100μg/tumour) significantly decreases tumour size from0.33g to 0.15g (p<0.05) compared to PBS-treated mice. Within tumour-infiltrating leukocytes, plasticity and cell polarization of TAMsare key aspects to define a final antitumoral (M1-like) or protumoral(M2-like) outcome and here we observed that pAU significantlydecreases the total number of M1-like macrophages (MHCIIhigh;CD206-) and M2-like macrophages (MHCIIlow; CD206+) the latterbeing the population accounting for most of the intratumoral IL10production as seen by FACS. We determined that both MHCII+ andMHCII- monocytes were a key source of intratumoral TNFα, whichwas upregulated after pAU treatment (p<0.05). Strikingly, when weevaluated the expression of PDL1, expressed by APCs and tumourcells, we observed a significant upregulation (p<0.05) of this ligandspecifically on MHCII- monocytes after the treatment with pAU andvery little impact on other tumour-infiltrating cells. Finally, most of theeffects described after pAU administration on the myeloid compartmentwere lost in IFNAR-/- mice, suggesting that pAU-induced typeI IFNs directly modulate myeloid cells in the tumour.Keywords: Immunotherapy, TLR3, PDL1, Monocytes