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

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

CABA

Congreso; Reunión Anual SAIC 2021; 2021

One of the main immunosuppressive mechanisms by which canceravoids eradication by the immune system is the expression ofPD-L1, the ligand for T-cell inhibitory receptor PD-1. PD-1 activationby PD-L1 leads to CD4+/CD8+ lymphocyte exhaustion, which is atthe focal point of today?s cancer immune therapies. However, littleis known about which other immunosuppression mechanisms aretriggered by tumor-intrinsic PD-L1 expression.To genetically address tumor-immune system interactions in a triplenegative 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 theprogression of EO771 tumors, which resembled immunosuppressionsignatures associated with poor prognosis in TNBC patients:an increase in pro-tumoral M2 macrophage polarization, a decreasein MHCII+ Antigen Presenting Cells (APCs) and a marked increaseof 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 editedEO771 lines KO for PD-L1, we found that tumor intrinsic PD-L1expression is required for tumor growth. Interestingly, we also foundthat PD-L1 expressed by the tumor cell exerts a general impact overthe tumoral immune infiltrate composition: a) it is required for thedifferentiation of M2 macrophages and for the enrichment of myeloidderived 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.All together, these data suggests that tumor-intrinsic PD-L1 plays akey role on TNBC tumor growth by triggering different immunosuppressivemechanisms in the tumor immune landscape. Using thiseditable EO771 model platform, we will be able to massively testtumoral PD-L1 synthetic interactions to identify candidate genetictargets to overcome PD-1/PD-L1 resistance in TNBC.