Fauvre Alexandra, Ursino Chiara, Garambois Veronique, Culerier Elodie, Milazzo Louis-Antoine, Vezzio-Vié Nadia, Jeanson Laura, Marchive Candice, Andrade Augusto Faria, Combes Eve, Atis Salima, Lossaint Gérald, Quenet François, Michaud Henri-Alexandre, Khellaf Lakhdar, Corbeau Ileana, Tosi Diego, Houede Nadine, Bonnefoy Nathalie, Sgarbura Olivia, Gongora Céline, Faget Julien
Résistance aux traitements et thérapies innovantes, Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier (UM), CNRS, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.
Immunity and Cancer Team, Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier (UM), Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.
J Immunother Cancer. 2025 Mar 26;13(3):e010791. doi: 10.1136/jitc-2024-010791.
Colorectal cancer (CRC) is the third most common cancer type and one of the leading causes of cancer-related death worldwide. The treatment of advanced metastatic CRC relies on classical chemotherapy combinations (5-fluorouracil, oxaliplatin or irinotecan). However, their use is limited by the emergence of resistance mechanisms, including to oxaliplatin. In this context, we recently showed that the combination of oxaliplatin and ataxia telangiectasia and Rad3-related protein inhibition (VE-822) is synergistic and may have a potential therapeutic effect in metastatic CRC management.
In this study, we investigated the role of the VE-822+oxaliplatin (Vox) combination on the immune response and its potential synergy with an anti-programmed-cell Death receptor-1 (PD-1) antibody. We used cell lines and organoids from metastatic CRC to investigate in vitro Vox efficacy and orthotopic syngeneic mouse models of metastatic CRC to assess the efficacy of Vox+anti-PD-1 antibody and identify the involved immune cells.
The Vox+anti-PD-1 antibody combination completely cured tumor-bearing mice and protected them from a rechallenge. Vox was associated with a reduction of tumor-infiltrated neutrophils, CD206 macrophages and regulatory T cells. Vox also induced a deep depletion of blood neutrophils. The increased bone marrow granulopoiesis failed to compensate for the Vox-mediated mature neutrophil depletion. Neutrophil depletion using a mouse recombinant anti-Ly6G antibody partially mimicked the Vox effect on the tumor microenvironment, but to a lower extent compared with the Vox+anti-PD-1 antibody combination. Vox, but not neutrophil depletion, led to the emergence of an Ly6C PD-1 CD8 T-cell population in the blood and spleen of tumor-harboring mice. These cells were proliferating, and expressed IFN-γ, CD62L, CXCR3 and Eomes. Moreover, the proportion of tumor antigen-specific T cells and of CD122 BCL6 T cells, which shared phenotypic characteristics with stem-like CD8 T cells, was increased in treated mice.
Our work strongly suggests that the Vox+anti-PD-1 antibody combination might significantly improve survival in patients with metastatic and treatment-refractory CRC by acting both on cancer cells and CD8 T cells.
结直肠癌（CRC）是全球第三大常见癌症类型，也是癌症相关死亡的主要原因之一。晚期转移性CRC的治疗依赖于经典的化疗组合（5-氟尿嘧啶、奥沙利铂或伊立替康）。然而，它们的使用受到耐药机制出现的限制，包括对奥沙利铂的耐药。在此背景下，我们最近发现奥沙利铂与共济失调毛细血管扩张症和Rad3相关蛋白抑制（VE-822）的联合具有协同作用，可能对转移性CRC的治疗具有潜在疗效。
在本研究中，我们研究了VE-822+奥沙利铂（Vox）组合对免疫反应的作用及其与抗程序性细胞死亡受体-1（PD-1）抗体的潜在协同作用。我们使用转移性CRC的细胞系和类器官来研究体外Vox的疗效，并使用转移性CRC的原位同基因小鼠模型来评估Vox+抗PD-1抗体的疗效，并确定所涉及的免疫细胞。
Vox+抗PD-1抗体组合完全治愈了荷瘤小鼠，并使其免受再次攻击。Vox与肿瘤浸润中性粒细胞、CD206巨噬细胞和调节性T细胞的减少有关。Vox还导致血液中性粒细胞深度减少。骨髓粒细胞生成增加未能补偿Vox介导的成熟中性粒细胞减少。使用小鼠重组抗Ly6G抗体消耗中性粒细胞部分模拟了Vox对肿瘤微环境的作用，但与Vox+抗PD-1抗体组合相比程度较低。Vox而非中性粒细胞消耗导致荷瘤小鼠血液和脾脏中出现Ly6C PD-1 CD8 T细胞群体。这些细胞在增殖，并表达IFN-γ、CD62L、CXCR3和Eomes。此外，在治疗小鼠中，与干细胞样CD8 T细胞具有共同表型特征的肿瘤抗原特异性T细胞和CD122 BCL6 T细胞的比例增加。
我们的工作强烈表明，Vox+抗PD-1抗体组合可能通过作用于癌细胞和CD8 T细胞，显著提高转移性和难治性CRC患者的生存率。
