Denis Musquer Marie, Jouand Nicolas, Pere Morgane, Lamer Juliette Eugène, Bézieau Stéphane, Matysiak Tamara, Faroux Roger, Caroli Bosc François-Xavier, Rousselet Marie-Christine, Leclair François, Mosnier Jean-François, Toquet Claire, Gervois Nadine, Bossard Céline
Department of Pathology, University Hospital of Nantes, Nantes, France.
Université de Nantes, Inserm, CRCINA, Nantes, France.
Front Oncol. 2021 Jun 15;11:684478. doi: 10.3389/fonc.2021.684478. eCollection 2021.
Antibody-dependent cellular cytotoxicity (ADCC) in the anti-tumor effect of cetuximab in metastatic colorectal cancer (mCRC) is only based on the impact of FcγRIIIA (CD16) polymorphisms as predictive of therapeutic response. However, nature, density and therapeutic impact of FcγRIIIA (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 . 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 FcγRIIIA (CD16) immune cells, 2) the expression profile of HLA-E/β2m 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 FcγRIIIA (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/β2m, 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 FcγRIIIA (CD16) in mCRC patients, to boost cetuximab-mediated ADCC in wild-type mCRC patients. The preferential overexpression of HLA-E/β2m 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- FcγRIIIA/EGFR bispecific antibodies as a promising therapeutic perspective in wild-type mCRC patients.
西妥昔单抗在转移性结直肠癌（mCRC）抗肿瘤作用中的抗体依赖性细胞毒性（ADCC）仅基于FcγRIIIA（CD16）多态性对治疗反应的预测影响。然而，肿瘤中FcγRIIIA（CD16）效应细胞的性质、密度及其治疗影响仍缺乏充分的文献记载。此外，仅证实了新的抑制性CD94-NKG2A免疫检查点的激活可抑制自然杀伤细胞诱导的西妥昔单抗介导的ADCC。这项多中心研究旨在对一组接受西妥昔单抗治疗的mCRC患者的配对原发性和转移性组织样本进行检测，以确定：1）FcγRIIIA（CD16）免疫细胞的性质和密度；2）肿瘤细胞上HLA-E/β2m的表达谱以及CD94免疫细胞的密度；3）它们对西妥昔单抗客观反应和生存的影响。我们证明，FcγRIIIA（CD16）上皮内免疫细胞主要对应肿瘤相关中性粒细胞（TAN），其在转移灶中的高密度与对西妥昔单抗的更好反应显著相关，且与CD94/NKG2A抑制性免疫检查点的表达无关。然而，与原发性肿瘤相比，HLA-E/β2m在转移灶中优先过表达，并与CD94肿瘤浸润淋巴细胞（TIL）相关，这与较差的总生存期有关。总之，这些结果有力地支持在mCRC患者中使用针对表皮生长因子受体（EGFR）和FcγRIIIA（CD16）的双特异性抗体，以增强野生型mCRC患者中西妥昔单抗介导的ADCC。HLA-E/β2m在转移灶中优先过表达，与CD94 TIL相关且预后不良，这为在野生型mCRC患者中使用人源化抗NKG2A抗体莫纳利珠单抗抑制这一新的免疫检查点提供了令人信服的依据，莫纳利珠单抗与抗FcγRIIIA/EGFR双特异性抗体联合使用有望成为一种治疗方案。
