High-Density Of Fc Gamma Riiia(+) (Cd16(+)) Tumor-Associated Neutrophils In Metastases Improves The Therapeutic Response Of Cetuximab In Metastatic Colorectal Cancer Patients, Independently Of The Hla-E/Cd94-Nkg2a Axis

Antibody-dependent cellular cytotoxicity (ADCC) in the anti-tumor effect of cetuximab in metastatic colorectal cancer (mCRC) is only based on the impact of Fc gamma RIIIA (CD16) polymorphisms as predictive of therapeutic response. However, nature, density and therapeutic impact of Fc gamma RIIIA(+) (CD16) effector cells in tumor remain poorly documented. Moreover, the inhibition of cetuximab-mediated ADCC induced by NK cells by the engagement of the new inhibitory CD94-NKG2A immune checkpoint has only been demonstrated in vitro. This multicentric study aimed to determine, on paired primary and metastatic tissue samples from a cohort of mCRC patients treated with cetuximab: 1) the nature and density of Fc gamma RIIIA(+) (CD16) immune cells, 2) the expression profile of HLA-E/beta 2m by tumor cells as well as the density of CD94(+) immune cells and 3) their impact on both objective response to cetuximab and survival. We demonstrated that Fc gamma RIIIA(+) (CD16) intraepithelial immune cells mainly correspond to tumor-associated neutrophils (TAN), and their high density in metastases was significantly associated with a better response to cetuximab, independently of the expression of the CD94/NKG2A inhibitory immune checkpoint. However, HLA-E/beta 2m, preferentially overexpressed in metastases compared with primary tumors and associated with CD94(+) tumor infiltrating lymphocytes (TILs), was associated with a poor overall survival. Altogether, these results strongly support the use of bispecific antibodies directed against both EGFR and Fc gamma RIIIA (CD16) in mCRC patients, to boost cetuximab-mediated ADCC in RAS wild-type mCRC patients. The preferential overexpression of HLA-E/beta 2m in metastases, associated with CD94(+) TILs and responsible for a poor prognosis, provides convincing arguments to inhibit this new immune checkpoint with monalizumab, a humanized anti-NKG2A antibody, in combination with anti- Fc gamma RIIIA/EGFR bispecific antibodies as a promising therapeutic perspective in RAS wild-type mCRC patients.