TUMORAL PD-L1 MODULATES CD206+ MACROPHAGE IMMUNOSUPPRESION DURING BREAST CANCER PROGRESSION

AGUIRRE PAULA; CASTILLO LILIAN; PALAVECINO MARCOS; GONZALEZ PAULA; VALLONE SABRINA; SUBAN AGUSTINA; MEISS ROBERTO; RODRIGUEZ SEGUI SANTIAGO; COSO OMAR; WERTHEIMER EVA; KORDON EDITH; SIMIAN MARINA; ERRASTI ANDREA; CARRERA SILVA EUGENIO; DE LA MATA MANUEL; GATTELLI ALBANA; FEDEDA JUAN PABLO

Mar del Plata

Congreso; Reunión Anual SAIC 2023; 2023

SAIC

One of the main immunosuppressive mechanisms during tumorprogression is the expression of PD-L1, the ligand for T-cell inhibitoryreceptor PD-1. Despite PD-1 is also expressed in the myeloidlineage, it is not clear which macrophage-specific immune evasionmechanisms are modulated by tumor cell PD-L1. To interrogate this,we generated a PD-L1 KO TNBC-like tumor model in the murineEO771 cell line using CRISPR/Cas9 editing, allowing us to profilethe immune infiltrates of the tumoral microenvironment (TME) invivo. Profiling tumor growth in WT vs. PD-L1 KO tumors, we foundthat tumoral PD-L1 is partially required for EO771 tumor growth. Usingflow cytometry (FC) to characterize the immune infiltrates of earlyvs late-stage WT tumors, we found a decrease in F480h CD206+TAMs in late-stage tumors, suggesting that inhibition of CD206+polarization is involved in immune evasion. Interestingly, analyzinglate-stage PD-L1 KO vs WT tumors, we found that tumoral PD-L1inhibits CD206+ macrophage polarization. Furthermore, WT tumorprogression triggered PD-1+ and MHCII+ expression in CD206+TAMs. Comparing PD-L1 KO vs WT tumors, we found that tumoralPD-L1 promotes MHCII expression in CD206+ TAMs, suggestingthat PD-L1 fosters antigen presentation by MHCII in vivo. On thecontrary, FC analysis of in vitro experiments showed that direct contactof tumoral PD-L1 inhibits MHCII expression in CD206+ macrophages,suggesting that indirect TME mechanisms compensate theimmunosuppressive inhibition of MHCII mediated by tumoral PD-L1.Interestingly, using FC to analyze GFP+ tumor cell phagocytosis inCD11b+ F480+ TAMs, we found that tumoral PD-L1 directly suppressesphagocytosis both in vivo and in vitro. Altogether, thesedata suggest that tumor-intrinsic PD-L1 plays a key role in TNBCprogression by triggering immune suppression mechanisms inCD206+ TAMs. By interrogating these non-canonical mechanisms,we could gain insights into novel mechanisms of resistance to PDL1/PD-1 therapies.