Radiation therapy (RT) has the potential to activate the tumor-microenvironment (TME) and promote the efficacy of immune checkpoint blockade therapy. Tumor cell-intrinsic expression of cyclic GMP-AMP ...synthase (cGAS)-stimulator of interferon genes (STING) plays an important role in regulations of radiation-induced activation of immune cells in the TME. However, the role of tumor cell-intrinsic cGAS-STING in radiation-mediated remodeling of the TME in esophageal squamous cell carcinoma (ESCC) is not completely understood; thus, we investigated its effect on the radiation-mediated remodeling of the TME in ESCC.
We assessed the effect of tumor cell-intrinsic cGAS-STING on the expression of mediators of the immune system, including type I interferon, T-cell chemo-attractants, colony-stimulating factor-1, and interleukin 34 (IL-34), induced by radiation in ESCC cell lines. We also quantified the association between tumor cell-intrinsic expression of cGAS-STING and infiltrations of immune cells, including CD8
T cells and CD163
M2-tumor-associated macrophages (TAMs), in ESCC tissues before and after neoadjuvant chemo-RT (n = 47).
We found that tumor cell-intrinsic expression of cGAS-STING was involved in radiation-induced infiltration of CD8
T cells and expression of type I interferon and T-cell chemo-attractants in ESCC cells. Surprisingly, tumor cell-intrinsic cGAS-STING was also involved in radiation-triggered infiltration and/or M2-polarization of CD163
TAMs and expression of IL-34, an important cytokine for recruitment and M2-polarization of TAMs, in ESCC cells. The number of CD163
M2-TAMs was significantly associated with IL-34 expression in tumor cells in irradiated ESCC tissues.
The tumor cell-intrinsic expression of cGAS-STING is essential for radiation-induced activation of immune cells in the TME, but it is also involved in the recruitment of tumor-promoting M2-TAMs in ESCC. Therefore, blocking of M2-TAM infiltration by targeting IL-34 might improve the efficacy of RT and combination therapy of RT with immune checkpoint inhibitors in ESCC.
Deficient mismatch repair (dMMR)/microsatellite instability (MSI) colorectal cancer (CRC) has high immunogenicity and better prognosis compared with proficient MMR (pMMR)/microsatellite stable (MSS) ...CRC. Although the activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been considered to contribute to the high number of CD8
+
TILs, its role in dMMR/MSI CRC is largely unknown. In this study, to examine the role of the cGAS-STING pathway on the recruitment of CD8
+
TILs in dMMR/MSI CRC, we used public datasets and clinical tissue samples in our cohorts to evaluate the expression of cGAS, STING, and CD8
+
TILs in pMMR/MSS and dMMR/MSI CRCs. According to the analysis of public datasets, the expression of cGAS-STING, CD8 effector gene signature, and CXCL10-CCL5, chemoattractants for CD8
+
TILs which regulated by the cGAS-STING pathway, was significantly upregulated in dMMR/MSI CRC, and the expression of cGAS-STING was significantly associated with the expression of CD8 effector gene signature. Immunohistochemistry staining of the clinical tissue samples (
n
= 283) revealed that cGAS-STING was highly expressed in tumor cells of dMMR CRC, and higher expression of cGAS-STING in tumor cells was significantly associated with the increased number of CD8
+
TILs. Moreover, we demonstrated that the downregulation of MMR gene in human CRC cell lines enhanced the activation of the cGAS-STING pathway. Taken together, for the first time, we found that dMMR/MSI CRC has maintained a high level of cGAS-STING expression in tumor cells, which might contribute to abundant CD8
+
TILs and immune-active TME.
Colorectal cancer (CRC) develops through chromosomal instability (CIN) or microsatellite instability (MSI) due to deficient mismatch-repair (dMMR). We aimed to characterise novel cancer-associated ...genes that are downregulated upon malignant transformation in microsatellite stable (MSS) CRCs, which typically exhibit CIN with proficient mismatch-repair (pMMR).
Comprehensive screening was conducted on adenomas, MSI/MSS CRCs and cell lines, followed by copy number analysis, and their genetic and prognostic relevance was confirmed in microarray and RNA-seq cohorts (n = 3262, in total). Immunohistochemistry for SH2D4A was performed in 524 specimens of adenoma, carcinoma in situ and dMMR/pMMR CRC. The functional role of SH2D4A was investigated using CRC cell lines.
A set of 11 genes, including SH2D4A, was downregulated during the adenoma-carcinoma sequence in MSS/CIN CRCs, mainly due to chromosome 8p deletions, and their negative prognostic impact was validated in independent cohorts. All adenomas were SH2D4A positive, but a subset of CRCs (5.3%) lacked SH2D4A immunohistochemical staining, correlating with poor prognosis and scarce T cell infiltration. SH2D4A depletion did not affect cell proliferation or IL-6-induced STAT3 phosphorylation.
Our findings suggest that downregulation of multiple genes on chromosome 8p, including SH2D4A, cooperatively contribute to tumorigenesis, resulting in the immune cold tumour microenvironment and poor prognosis.
Abstract Activating antibody-dependent cellular cytotoxicity (ADCC) by targeting claudin-18 isoform 2 (CLDN18.2) using zolbetuximab, a monoclonal antibody against CLDN18.2, has been considered a ...promising novel therapeutic strategy for gastric cancer (GC). However, the impact of CLDN18.2 expression on natural killer (NK) cells and monocytes/macrophages—crucial effector cells of ADCC—in GC has not been fully investigated. In the present study, we assessed the impact of CLDN18.2 expression on clinical outcomes, molecular features, and the frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, in GC by analyzing our own GC cohorts. The expression of CLDN18.2 did not significantly impact clinical outcomes of GC patients, while it was significantly and positively associated with Epstein–Barr virus (EBV) status and PD-L1 expression. The frequencies of tumor-infiltrating NK cells and macrophages, as well as peripheral blood NK cells and monocytes, were comparable between CLDN18.2-positive and CLDN18.2-negative GCs. Importantly, both CLDN18.2 expression and the number of tumor-infiltrating NK cells were significantly higher in EBV-associated GC compared to other molecular subtypes. Our findings support the effectiveness of zolbetuximab in CLDN18.2-positive GC, and offer a novel insight into the treatment of this cancer type, highlighting its potential effectiveness for CLDN18.2-positive/EBV-associated GC.
Proximal gastrectomy is a widely performed procedure that has become more common with an increasing number of proximal gastric cancer cases. Several types of reconstructive procedures after proximal ...gastrectomy have been developed, and it remains controversial which procedure is the most advantageous with regard to the preservation of postoperative gastric stump function and nutritional status. In the present study, we retrospectively analyzed reconstructive procedures in a consecutive case series for proximal gastrectomy, primarily focusing on postoperative body weight maintenance, nutritional status, and gastric remnant functional preservation.
We enrolled 69 patients who had undergone proximal gastrectomy for gastric cancer in our institute between 2005 and 2020. Short-term complications, preservation of gastric remnant functions, nutritional status, and post-operative weight changes were compared.
After proximal gastrectomy, the numbers of patients who underwent direct esophago-gastrostomy, jejunal interposition, double tract reconstruction, and the double flap technique were 9, 10, 14, and 36, respectively. The patients in whom the double flap technique was performed suffered no reflux esophagitis after surgery. Prevalence of gastric residual at 12 months after surgery was lowest in the double flap technique group. Moreover, the double flap technique group had a better tendency regarding post-operative changes of serum albumin ratios. Furthermore, the post-operative body weight change ratio of the double flap technique group was smallest among all groups and was significantly better than that of the double tract group.
The double flap technique after proximal gastrectomy was considered the most effective technique for reconstruction which leads to better bodyweight maintenance, and results in less reflux esophagitis.
Background
HER2 signaling might be involved in the regulation of immune cell activation in the tumor microenvironment (TME) of gastric cancer (GC). However, the relationship between HER2 status and ...immune cell condition in the HER2-positive GC TME is not clearly understood.
Methods
To investigate the effect of HER2 signaling on the activation of the cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contributes to immune cell activation in the GC TME, we evaluated the associations among the expressions of HER2, cGAS–STING, and the number of CD8
+
tumor-infiltrating lymphocytes (TIL) by considering HER2 heterogeneity in HER2-positive GC tissues. We also examined the effect of HER2 signaling on the activation of STING signaling in vitro using human HER2-positive GC cell lines.
Results
The expression of HER2 is highly heterogeneous in HER2-positive GC tissues, and we found that the number of CD8
+
TIL in HER2 high areas was significantly lower than that in HER2 low areas in HER2-positive GC tissues. Intriguingly, the tumor cell-intrinsic expression of STING, but not cGAS, was also significantly lower in the HER2 high areas than the HER2 low areas in HER2-positive GC tissues. Moreover, in vitro experiments, we demonstrated that the blockade of HER2 signaling increased the expression of STING and its target genes, including
IFNB1
,
CXCL9/10/11
, and
CCL5
, in HER2-positive GC cell lines.
Conclusions
Our results suggest that HER2 signaling might suppress immune cell activation in the GC TME by inhibiting STING signaling in tumor cells in HER2-positive GC.
The tumor microenvironment (TME) plays a key role in the efficacy of neoadjuvant chemotherapy (NAC) in solid tumors including esophageal squamous cell carcinoma (ESCC). However, the TME profile of ...ESCC treated with NAC is not fully understood. In this study, we investigated the effect of NAC on the TME especially tumor-associated macrophages (TAM), the important immunosuppressive components of the TME, in ESCC. We quantified the expression of CD163, a crucial marker of TAM, in pretherapeutic biopsy and surgically resected ESCC specimens from patients who received NAC (
= 33) or did not receive NAC (
= 12). We found that NAC dramatically increased the expression of CD163 on TAMs in ESCC. Colony-stimulating factor 1 (CSF-1) and IL34 are crucial cytokines that recruit monocytes into tumor sites and differentiate them into TAMs. Interestingly, NAC significantly upregulated the expression of IL34 but not CSF-1 on tumor cells, and the frequencies of CD163
TAMs were significantly correlated with IL34 expression in ESCC after NAC. The expression of IL34 in NAC-nonresponsive patients was significantly higher than that in NAC-responsive patients, and patients with IL34-high ESCC exhibited worse prognosis as compared with patients with IL34-low ESCC. We also demonstrated that 5-fluorouracil (5-FU)/cisplatin preferentially increased mRNA expression of IL34 on human ESCC cell lines. Human peripheral blood monocytes co-cultured with ESCC cells treated with 5-FU/cisplatin increased the expression of CD163, which was attenuated by the treatment with CSF-1R inhibitors. These data suggest that IL34 expression by NAC shifts the TME toward CD163
TAM-rich immunosuppressive and chemo-insensitive microenvironment in ESCC. IMPLICATIONS: The blockade of IL34 signaling may offer a novel therapeutic strategy against chemoresistance in ESCC by inhibiting M2-TAM polarization.
In order to develop a biomarker predicting the efficacy of treatments for patients with esophageal squamous cell carcinoma (ESCC), we evaluated the subpopulation of T cells in ESCC patients treated ...with chemotherapy (CT), chemoradiotherapy (CRT), and nivolumab therapy (NT). Fifty-five ESCC patients were enrolled in this study, and peripheral blood samples were collected before and after CT or CRT and during NT. Frequencies of memory, differentiated, and exhausted T cells were evaluated using flow cytometry among cStages, treatment strategies, pathological responses of CT/CRT, and during NT. The frequencies of PD-1
or TIM-3
CD4
T cells were significantly higher in patients with cStage IV. PD-1
CD4
and TIM-3
CD8
T-cell populations were significantly higher in patients treated with CRT but were not associated with treatment response. The frequencies of both CD4
and CD8
CD45RA
CD27
CD127
central memory T cells (T
) were significantly decreased during the course of NT in the progressive disease group. Taken together, the alteration in frequency of CD45RA
CD27
CD127
T
during NT may be a biomarker to predict its therapeutic response in ESCC patients.
Background:Postoperative pneumonia is one of the major complications after esophagectomy. The aim of this study was to determine whether bacterial cultures before esophagectomy could predict ...occurrence of postoperative pneumonia and help treatment strategies for postoperative pneumonia. Methods:Sixty-nine patients who underwent subtotal esophagectomy at Fukushima Medical University Hospital between January 2017 and May 2021 were included in this study. We collected sputum, oral, and/or nasopharyngeal swabs for bacterial culture preoperatively from all patients and from those who were suspected of postoperative pulmonary infections. We compared cultured pathogenic bacteria obtained preoperatively and postoperatively from patients who developed postoperative pneumonia, and investigated their association with incidence of postoperative pneumonia. Results:Postoperative pneumonia occurred in 22 of 69 patients (31%), including 13 cases of severe pneumonia with a Clavien-Dindo classification of grade IIIa or higher. Multivariate analysis revealed that longer operative duration (for 30 minutes increase;odds ratio 1.27, 95% CI 1.01-1.51, p=0.039) and positivity for preoperative bacterial culture (odds ratio 5.03, 95% CI 1.31-19.2, p=0.018) were independent risk factors for severe postoperative pneumonia, but not for all incidences of postoperative pneumonia. Of note, in only 5 of the 22 patients with pneumonia, the same pathogenic species were detected preoperatively and after the onset of pneumonia.Conclusions:Our results imply that preoperative bacterial culture may be useful to predict severe postoperative pneumonia. However, it may not be useful in determining pathogenic bacteria responsible for postoperative pneumonia.
Systemic inflammation has been reported to be associated with cancer progression and metastasis. Systemic inflammation score (SIS), calculated from preoperative serum albumin level and ...lymphocyte-to-monocyte ratio, has been shown to be a novel prognostic factor for several types of tumors. This study aimed to evaluate the prognostic value of the SIS in patients with pT2-4 resectable gastric cancer (GC).
Total 97 patients with pT2-4 GC who underwent curative surgery from 322 cases between 2009 and 2015 in Fukushima Medical University Hospital were included. We performed univariate and multivariate analyses to evaluate the usefulness of preoperative SIS and other prognostic factors for relapse-free survival (RFS) and overall survival (OS).
The higher SIS score was associated with undifferentiated cancer and recurrence. Univariate analysis of RFS identified deeper tumor invasion and higher SIS were significant risk factors and multivariate analysis revealed that both of them were independent prognostic factors for RFS. As for OS, age, tumor invasion, SIS and LNR were significantly correlated with RFS. In multivariate analysis, tumor invasion, SIS and LNR were independent prognostic factors for OS.
SIS was an independent prognostic factor for RFS and OS in pT2-4 resectable gastric cancer patients who underwent curative gastrectomy.
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