TUMORAL PD-L1 ORCHESTRATES DIFFERENT TUMOR-INDUCED IMMUNOSUPPRESSION MECHANISMS DURING BREAST CANCER PROGRESSION

PAULA ANABELLA AGUIRRE; MARCOS DANIEL PALAVECINO; ADRIANO BERTELLI; JUAN PABLO FEDEDA

Congreso; Reunión Conjunta SAIC. SAI. AAFE. NANOMED-AR; 2021

One of the main immunosuppressive mechanisms by which cancer avoids eradication by theimmune system is the expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1. PD-1activation by PD-L1 leads to CD4+/CD8+ lymphocyte exhaustion, which is at the focal point oftoday’s cancer immune therapies. However, little is known about which other immunosuppressionmechanisms are triggered by tumor-intrinsic PD-L1 expression.To genetically address tumor-immune system interactions in a triple negative breast cancer(TNBC) model, we developed a CRISPR/Cas9 expressing TNBC-like EO771 cell line platform.Using flow cytometry, we characterized the immune response associated with the progression ofEO771 tumors, which resembled immunosuppression signatures associated with poor prognosisin TNBC patients: an increase in pro-tumoral M2 macrophage polarization, a decrease in MHCII+Antigen Presenting Cells (APCs) and a marked increase of T-cell exhaustion.To test the role of tumoral PD-L1 in tumor-mediated immune escape, we generated PD-L1 KOEO771 cell lines. Using CRISPR/Cas9 edited EO771 lines KO for PD-L1, we found that tumorintrinsic PD-L1 expression is required for tumor growth. Interestingly, we also found that PD-L1expressed by the tumor cell exerts a general impact over the tumoral immune infiltratecomposition: a) it is required for the differentiation of M2 macrophages and for the enrichment ofmyeloid derived suppressor cells and b) in the T-cell compartment, unexpectedly, tumoral PD-L1is needed to exhaustion of effector CD4+ but not cytotoxic CD8+ cells.All together, these data suggests that tumor-intrinsic PD-L1 plays a key role on TNBC tumorgrowth by triggering different immunosuppressive mechanisms in the tumor immune landscape.Using this editable EO771 model platform, we will be able to massively test tumoral PD-L1synthetic interactions to identify candidate genetic targets to overcome PD-1/PD-L1 resistance inTNBC