Neoadjuvant chemotherapy enhances anti-tumor immune response of tumor microenvironment in human esophageal squamous cell carcinoma

Okuda, Sho; Ohuchida, Kenoki; Nakamura, Shoichi; Tsutsumi, Chikanori; Hisano, Kyoko; Mochida, Yuki; Kawata, Jun; Ohtsubo, Yoshiki; Shinkawa, Tomohiko; Iwamoto, Chika; Torata, Nobuhiro; Mizuuchi, Yusuke; Shindo, Koji; Moriyama, Taiki; Nakata, Kohei; Torisu, Takehiro; Morisaki, Takashi; Kitazono, Takanari; Oda, Yoshinao; Nakamura, Masafumi

doi:10.1016/j.isci.2023.106480

Cited by 5 publications

(1 citation statement)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To achieve this, interest has turned to the symbiotic relationship between the tumor immune microenvironment (TIME) and neoadjuvant therapies. Solid tumors comprise of a complex and diverse mixture of noncancerous cell types and stromal tissue and this environment modulates response to systemic therapy and vice-versa [10][11][12] . For instance, treatment with PD-L1 antibodies results in the modulation of tumor speci c T cell response within the TIME and is associated with improved pathological response in multiple solid malignancies 13,14 .…”

Section: Introductionmentioning

confidence: 99%

A phase 2 trial of peri-operative avelumab and chemotherapy for locally advanced gastro-esophageal adenocarcinoma: Association of AGR2/AP-1 complex CD8 T-cells and M2-Tumour Associated Macrophages with treatment response

Ferri,

Alcindor,

Tankel

et al. 2023

Preprint

View full text Add to dashboard Cite

Perioperative chemo-immunotherapy represents a promising treatment modality for locally advanced gastroesophageal adenocarcinoma (GEA). However, the potential of these novel treatments has yet to be realized and efforts to identify patients who would benefit for targeted therapies have been unsuccessful. Herein we present the clinical results of a phase 2 trial combining neoadjuvant docetaxel, cisplatin, 5FU and the PD-L1 inhibitor avelumab for patients with locally advanced GEA and describe the tumor inflammatory microenvironment associated with response. Fifty-one patients were enrolled and received neoadjuvant therapy with 50 proceeding to surgery. Grade 3-4 adverse events occurred in 40% of patients. Major pathological response occurred in 9/50 patients (18%). No correlation was found between tumor regression and PD-L1, MMR protein expression or reduction in standard uptake values on PET. Multiplex immunohistochemistry revealed CD8+ T cell proliferation in post-operative specimens, particularly among individuals who responded well to the treatment, and a greater predominance of M2-Tumour Associated Macrophages in poor-responders. Single cell transcriptomic profiling of treatment naïve tumors also indicated differential gene expression among T cells, and in particular higher differences in CD8+ central memory T cells in responders when compared to non-responders to neoadjuvant therapy. We found the expression of AGR2 of genes belonging to the activator protein-1 (AP-1) complex, such as JUND, was closely associated with pathological response. This finding provides evidence of novel predictors of response to neoadjuvant chemo-immunotherapy and identifies potential direction to personalize neoadjuvant therapy with a view to improving treatment response. Trial registration information: The study is registered on www.clinicaltrials.gov URL: https://clinicaltrials.gov/ct2/show/NCT03288350 (NCT03288350)

show abstract