Impacts of tumor microenvironment during neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma

• Published in: Cancer science 2024-08, Vol.115 (8), p.2819-2830
• Main Authors: Sugawara, Kotaro, Fukuda, Takashi, Murakami, Chiaki, Oka, Daiji, Yoshii, Takako, Amori, Gulanbar, Ishibashi, Kumiko, Kobayashi, Yasuhito, Hara, Hiroki, Kanda, Hiroaki, Motoi, Noriko
• Format: Article
• Language: English
• Subjects: Adult; Aged; Algorithms; Apoptosis; B7-H1 Antigen - metabolism; Cancer therapies; CD20 antigen; CD4 antigen; CD8 antigen; Chemotherapy; Chemotherapy, Adjuvant - methods; Clinical outcomes; Cloning; Esophageal cancer; Esophageal carcinoma; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - mortality; Esophageal Neoplasms - pathology; esophageal squamous cell carcinoma; Esophageal Squamous Cell Carcinoma - drug therapy; Esophageal Squamous Cell Carcinoma - immunology; Esophageal Squamous Cell Carcinoma - metabolism; Esophageal Squamous Cell Carcinoma - mortality; Esophageal Squamous Cell Carcinoma - pathology; Female; Foxp3 protein; Humans; immune checkpoint inhibitor; Immune checkpoint inhibitors; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Male; Medical prognosis; Middle Aged; neoadjuvant chemotherapy; Neoadjuvant Therapy - methods; PD-L1 protein; Prognosis; Radiation therapy; Squamous cell carcinoma; Surgery; Tumor microenvironment; Tumor Microenvironment - immunology; Tumors
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16203

With the advent of immune checkpoint inhibitors (ICIs), a better understanding of tumor microenvironment (TME) is becoming crucial in managing esophageal squamous cell carcinoma (ESCC) patients. We investigated the survival impact of TME status and changes in patients with ESCC who underwent neoadjuvant chemotherapy (NAC) followed by surgery (n = 264). We examined immunohistochemical status (CD4+, CD8+, CD20+, Foxp3+, HLA class‐1+, CD204+, and programmed death ligand‐1 [PD‐L1+]) on 264 pre‐NAC and 204 paired post‐NAC specimens. Patients were classified by their pre‐ and post‐NAC immune cell status and their changes following NAC. Our findings showed that pre‐NAC TME status was not significantly associated with survival outcomes. In contrast, post‐NAC TME status, such as low level of T cells, CD4+ T cells, and high PD‐L1 combined positive score (CPS), were significantly associated with poor overall survival (OS). Notably, TME changes through NAC exerted significant survival impacts; patients with consistently low levels of T cells, low levels of CD4+ T cells, or high levels of PD‐L1 (CPS) had very poor OS (3‐year OS: 35.5%, 40.2%, and 33.3%, respectively). Tumor microenvironment changes of consistently low T cells, low CD4+ T cells, and high PD‐L1 were independent predictors of poor OS in multivariate Cox hazards analyses, while factors indicating post‐NAC status (T cells, CD4+, and PD‐L1 [CPS]) alone were not. Therefore, we suggest that the consistently low T/high PD‐L1 group could benefit from additional therapies, such as ICIs, and the importance of stratification by the TME, which has recently been recognized. Tumor microenvironment after neoadjuvant chemotherapy (NAC), such as low T cells, low CD4+ cells, or high programmed death ligand‐1 [PD‐L1], were significantly associated with poor survival in patients with esophageal squamous cell carcinoma. Importantly, immune cell changes following NAC, such as consistently low T cells, consistently low CD4+ cells, or persistently high PD‐L1, were independent predictors for poor survival.