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

PAULA ANABELLA AGUIRRE; MARCOS DANIEL PALAVECINO; LILIAN FEDRA CASTILLO; SABRINA ALDANA VALLONE; ROBERTO MEISS; ADRIANO BERTELLI; AGUSTINA SUBAN; SANTIAGO RODRIGUEZ- SEGUÍ; OMAR ADRIAN COSO; EVA WERTHEIMER; EDITH CLAUDIA KORDON; MARINA SIMIAN; ANDREA EMILSE ERRASTI; MANUEL DE LA MATA; ALBANA GATTELLI; EUGENIO ANTONIO CARRERA- SILVA; JUAN PABLO FEDEDA

Buenos Aires

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2021; 2021

SAIC SAI AAFE Nanomed

One of the main immunosuppressive mechanisms by which cancer avoids eradication by the immune system is the expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1. PD-1 activation by PD-L1 leads to CD4+/CD8+ lymphocyte exhaustion, which is at the focal point of today?s cancer immune therapies. However, little is known about which other immunosuppression mechanisms aretriggered by tumor-intrinsic PD-L1 expression. To genetically address tumor-immune system interactions in the 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 of EO771 tumors, which resembled immunosuppression signatures associated with poor prognosis in 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 KO EO771 cell lines. Using CRISPR/Cas9 edited EO771 lines KO for PD-L1, we found that tumor intrinsic PD-L1 expression is required for tumor growth. Interestingly, we also found that PD-L1 expressed by the tumor cell exerts a general impact over the tumoral immune infiltrate composition: a) it is required for the differentiation of M2 macrophages and for the enrichment of myeloid-derived suppressor cells and b) in the T-cell compartment, unexpectedly, tumoral PD-L1 is needed to exhaustion of effector CD4+ but not cytotoxic CD8+ cells. Altogether, these data suggest that tumor-intrinsic PD-L1 plays a key role in TNBC tumor growth 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-L1 synthetic interactions to identify candidate genetic targets to overcome PD-1/PD-L1 resistance in TNBC.