Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma.

Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment. In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC. CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8+ T cells and conventional CD4+ T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1+CD8+ T cells in the tumor after CRT could predict a confirmed complete response and favorable survival. This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1+CD8+ T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment.

Habu T ，Kumagai S ，Bando H ，Fujisawa T ，Mishima S ，Kotani D ，Nakamura M ，Hojo H ，Sakashita S ，Kinoshita T ，Yano T ，Mitsunaga S ，Nishikawa H ，Koyama S ，Kojima T ... -  《-》

Prognostic value of immuno-inflammatory biomarkers in esophageal squamous cell carcinoma patients receiving immunotherapy combined with chemoradiotherapy and its association with immuno-genomic landscape.

The clinical significance of immuno-inflammatory indicators and the underlying biological basis in patients with esophageal squamous cell carcinoma (ESCC) who receive chemoradiotherapy (CRT) combined with immunotherapy remains unclear. This study aims to evaluate the prognostic value of immuno-inflammatory biomarkers, develop a prognostic model, and explore the underlying mechanisms. This study included 212 ESCC patients who received CRT and anti-PD-1 immunotherapy. Association between progression-free survival (PFS) and immuno-inflammatory biomarkers, including absolute lymphocyte count (ALC), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio was analyzed. A nomogram was built based on the independent prognostic factors identified using multivariable Cox regression model. Pre-treatment tumor samples from 47 patients were collected for RNA sequencing to investigate the immune-related tumor microenvironment. Patients experienced significant changes in immuno-inflammatory biomarkers during CRT, which gradually recovered after radiotherapy. Body mass index < 18.5 (HR, 1.85; P = 0.032), N3 stage (HR, 2.41; P = 0.002), high pre-CRT PLR (HR, 1.53; P = 0.037), low ALC nadir (HR, 1.84; P = 0.006), and high post-CRT NLR (HR, 2.12; P = 0.002) were independent prognostic factors for unfavorable PFS, which were incorporated into a nomogram with a concordance index of 0.70 (95% CI, 0.67-0.72). High-risk patients stratified by the nomogram had worse survival and were associated with lower levels of leukocyte and T cell activation, proliferation, and migration and less intratumoral immune cell infiltration. Pre-CRT PLR, ALC nadir during CRT, and post-CRT NLR were significantly associated with PFS in patients with ESCC receiving CRT and immunotherapy. A nomogram model with good prognostic ability was developed.

Cheng X ，Meng F ，Wang R ，Liu S ，Li Q ，Chen B ，Xi M ... -  《BMC CANCER》

Inflammatory markers correlate with lymphocytes infiltrating and predict immunotherapy prognosis for esophageal cancer.

Wang B ，Wang Z ，Wang K ，Shao Z ，Chen H ，Xu L ，Pan Y ，Zheng M ，Geng W ，Xu C ... -  《-》

Lympho-myeloid aggregate-infiltrating CD20(+) B cells display a double-negative phenotype and correlate with poor prognosis in esophageal squamous cell carcinoma.

According to morphological features, tumor-infiltrating B cells (TIL-Bs) can be classified as lympho-myeloid aggregates (LMAs) and tertiary lymphoid structures (TLSs). As a disease with high incidence and mortality, research on esophageal squamous cell carcinoma (ESCC) TIL-Bs is still unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TIL-Bs in ESCC. Based on CD20 immunohistochemical staining of 147 ESCC samples, the TIL-Bs at different anatomic subregions (intra-tumor (T), invasive margin (IM) and peri-tumor (P)) were quantified and correlated with survival by Kaplan-Meier analyses. We found that LMAs were widely distributed throughout the whole section and were associated with poor prognosis, especially those located in the T subregion, which was contrary to the positive clinical significance of TLSs. Based on the number of LMAs and TLSs, a four-level immune type was constructed as an independent predictor for survival. Using multiplexed immunofluorescence (mIF) staining, we found that the main phenotype of infiltrating B cells in LMAs was CD20+IgD-CD27- double-negative (DN) B cells. DN B cells were abundant in ESCC tumor tissue, and their high expression was related to shortened overall survival time. Subsequently, we demonstrate a close relationship between DN B cells and regulatory T cells (Tregs) using single cell RNA-seq data, bulk RNA-seq data and flow cytometry, and verified the spatial proximity of DN B cells and Tregs by mIF staining. Trajectory analysis and flow cytometry revealed that DN B cells highly expressed genes involved in the antigen processing and presentation pathway, such as HLA-DR. The abundance of DN B cells and LMAs in ESCC provides novel potential targets for optimal immunotherapy against ESCC.

Huang QF ，Wang GF ，Zhang YM ，Zhang C ，Ran YQ ，He JZ ，Wang G ，Xu XE ，Wang SH ，Wu JY ，Li EM ，Xu LY ... -  《-》

A novel disulfidptosis-related LncRNA prognostic risk model: predicts the prognosis, tumor microenvironment and drug sensitivity in esophageal squamous cell carcinoma.

Ye C ，Xu C ，Tang Y ，Qi Y ，Peng X ，Wei G ，Jiang L ... -  《BMC GASTROENTEROLOGY》