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Yu Tian,1,2,* Lei Zhang,3,* Nenghao Jin,1,2,* Zhiyi Wan,3 Henghui Zhang,4,5 Haizhong Zhang,2 Lei Zhang2 1Department of Stomatology, Medical School of Chinese PLA, Beijing, Peopleâs Republic of China; 2Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, Beijing, Peopleâs Republic of China; 3Department of Medicine, Genecast Biotechnology Co., Ltd, Wuxi, Jiangsu, Peopleâs Republic of China; 4Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, Peopleâs Republic of China; 5Ninth School of Clinical Medicine, Peking University, Beijing, China; School of Oncology, Capital Medical University, Beijing, Peopleâs Republic of China*These authors contributed equally to this workCorrespondence: Haizhong Zhang; Lei Zhang, Department of Stomatology, The First Medical Center, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing, Peopleâs Republic of China, Tel/Fax +86 1066938316, Email zhang126301@126.com; okdental@163.comAbstract: Immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab have been approved for the treatment of head and neck squamous cell carcinoma (HNSCC) and used in neoadjuvant immunotherapy in clinical trials. However, combination of ICIs with targeted therapy and chemotherapy was rarely used in pre-surgical HNSCC patients. Herein, we encountered three cases of patients with oral squamous cell carcinoma (OSCC) who all had good responses to neoadjuvant immunotherapy (anti-PD-1 inhibitors) combined with nimotuzumab (anti-EGFR monoclonal antibody) plus paclitaxel. Both Case 1 and Case 2 underwent the same neoadjuvant therapeutic combination (nivolumab, nimotuzumab and paclitaxel) and exhibited a marked tumor shrinkage even complete disappearance by radiological evaluation. Moreover, pathological response was observed in post-surgical tissues of Case 1. Additionally, Case 3 with tongue squamous cell carcinoma also had satisfactory tumor regression (complete healing of his tongue ulcer upon treatment) after receiving similar neoadjuvant therapy with sintilimab (another PD-1 inhibitor), nimotuzumab and paclitaxel. We characterized their potential causes behind favorable treatment outcomes. While there were differences in driver mutations and tumor mutation burden (TMB) identified in pre-treatment tumor tissues among the three patients, numerous CD68+ (macrophages) infiltrates were common for all the cases. Of note, the majority (> 80%) of the total macrophages were molecularly defined as PD-L1-positive macrophages. Given the high expression of PD-L1 in macrophages is associated with better immunotherapy outcomes, we propose that the high proportion of CD68+PD-L1+ cells in total macrophages alone could serve as a promising biomarker for neoadjuvant immunotherapy in combination with other therapies in HNSCC.Keywords: head and neck squamous cell carcinoma, oral squamous cell carcinoma, neoadjuvant immunotherapy, PD-L1, CD68, macrophage |