The synergistic effect of neoadjuvant immunotherapy and chemoradiotherapy in gastric adenocarcinoma is unclear. This phase II trial (NCT03631615) investigated this neoadjuvant combination in locally ...advanced adenocarcinoma of stomach or gastroesophageal junction. Thirty-six patients received capecitabine 850 mg/m
twice daily and simultaneous radiotherapy for 5 weeks, sandwiched by a 21-day cycle of oxaliplatin 130 mg/m
(day 1) plus capecitabine 1000 mg/m
twice daily (days 1-14), respectively, followed by surgery. Camrelizumab 200 mg (day 1) was given for 5 cycles since initiating chemotherapy. Primary endpoint was pathological complete response (pCR, ypT0) rate. Secondary endpoints included total pCR (tpCR, ypT0N0) rate, major pathological response (MPR, < 10% residual tumor cells) rate, margin-free (R0) resection rate, downstaging, progression-free survival (PFS), overall survival (OS), and safety. The pCR rate was 33.3% (95% CI, 18.6-51.0), meeting pre-specified endpoint. TpCR, MPR, and R0 resection rates were 33.3%, 44.4%, and 91.7%, respectively. Twenty-eight (77.8%) patients reached ypN0. Two-year PFS and OS rates were 66.9% and 76.1%, respectively. The most common grade 3-4 adverse event was decreased lymphocyte count (27 75.0%). Neoadjuvant camrelizumab plus concurrent chemoradiotherapy exhibits promising pathological response in patients with locally advanced gastric adenocarcinoma, with an acceptable safety profile.
Background
Tumor-associated macrophages (TAMs), the most predominant tumor-infiltrating immune cells, are emerging prognostic factors and therapeutic targets for personalized therapy against ...malignant neoplasms. We aimed to evaluate the prognostic significance of diametrically polarized TAMs in gastric cancer and generate a predictive nomogram to refine a risk stratification system.
Methods
We evaluated polarized functional status of infiltrated TAMs by immunohistochemical staining of CD68, CD11c, and CD206 in 180 consecutive gastric cancer patients from Zhongshan Hospital, Shanghai, China. Prognostic values were assessed in these patients. We created a predictive nomogram by integrating polarized TAMs with the TNM staging system for overall survival of gastric cancer patients.
Results
CD68
+
TAMs display polarized programs comprising CD11c
+
proinflammatory macrophages (M1) and CD206
+
immunosuppressive macrophages (M2) that configure versatile infiltration files in gastric cancer. CD11c
+
TAMs negatively correlated with lymph node metastasis (
p
= 0.012), whereas CD206
+
TAMs correlated with the Lauren classification (
p
= 0.031). No prognostic difference was observed for overall survival for CD68 density (high
vs
low,
p
= 0.1031), whereas high versus low CD11c density (
p
< 0.0001) and low
vs
high CD206 density (
p
= 0.0105) indicate better overall survival. Multivariate Cox regression analysis identified CD11c and CD206 as independent prognostic factors (
p
< 0.001 and
p
= 0.030, respectively), which could be integrated with the TNM staging system to generate a predictive nomogram for patient outcomes.
Conclusion
Infiltration of polarized TAMs, a novel identified independent prognostic factor, could be combined with the TNM stage to refine a risk stratification system and better stratify patients with different prognosis. Tipping TAMs to an antitumoral phenotype might be a promising therapeutic target for postoperative treatment.
Intratumoural CD103
CD8
T cells have been linked to prolonged survival in several malignancies. However, the clinical significance of CD103
CD8
T cells in gastric cancer remains unexplored.
Gastric ...cancer tissues from Zhongshan Hospital and data from Gene Expression Omnibus were obtained and analysed. Immunohistochemistry and flow cytometry were performed to detect the number and phenotypical characteristics of CD103
CD8
T cells. The effect of programmed cell death protein-1 (PD-1) blockade on CD103
CD8
T cells was evaluated with the use of an in vitro study based on fresh tumour tissues.
CD103
CD8
T cells predicted superior overall survival and provided better prognostic power than total CD8
T cells in gastric cancer. Patients with high CD103
CD8
T cell infiltration also gained more benefit from adjuvant chemotherapy. Flow cytometry analysis showed that CD103
CD8
T cells exerted superior anti-tumour effects with stronger retention capacity and cytotoxicity. Moreover, an in vitro study showed that CD103
CD8
T cells were more functionally restored after PD-1 blockade than CD103
CD8
T cells.
CD103
CD8
T cells might be a useful marker to predict prognosis and therapeutic efficacy for gastric cancer patients. Efforts to increase intratumoural CD103
CD8
T cell frequency might be a novel therapeutic strategy in gastric cancer.
Gastric cancer remains the third leading cause of cancer-related mortality worldwide, and invasion and metastasis of gastric cancer represent the major reason for its poor prognosis. In this study, ...we found that loss of the receptor for activated C-kinase 1 (RACK1) promoted the metastasis of gastric cancer by enhancing the autocrine expression of IL8 in vitro and in vivo. microRNA (miRNA; miR) array identified that RACK1 modulated the expression of a series of miRNAs, including the miR-302 cluster, and RACK1 modulated the IL8 expression and tumor invasion through miRNA-302c. Moreover, upregulation of IL8 in turn decreased the level of miRNA-302c and induced IL8 expression in a feedback manner. Tissue microarray also indicated that RACK1 was correlated with invasion/metastasis phenotype, IL8 expression, as well as 5-year survival in clinical cases of gastric cancer. Together, our results imply that loss of RACK1 in gastric cancer links epigenetics to inflammatory cytokines to promote tumor metastasis.
Adding anti-angiogenics to neoadjuvant chemotherapy for localized gastric cancer is recognized as a promising strategy, but its clinical value remains to be defined.
This single-center, single-arm, ...phase 2 trial included patients with locally advanced (cT3/4aN+M0) adenocarcinoma of the stomach or gastroesophageal junction (GEJ) who received three cycles of intravenous oxaliplatin (135 mg/m
on day 1), oral capecitabine (1000 mg/m
twice daily on days 1 to 14), and oral apatinib for 21 days (250 mg once daily in the first two cycles, and further increased to 500 mg daily in the third cycle based on whether any adverse event of grade 3 or worse occurred), and an additional cycle of oxaliplatin plus capecitabine, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was the proportion of patients who achieved an objective response according to RECIST version 1.1.
Between April 28, 2017, and October 23, 2019, 37 patients were screened and 35 participants were included. Of the 32 patients assessable for efficacy and safety, objective responses were achieved in 25 (78.1%; 95% confidence interval CI, 60.0% to 90.7%) patients. Thirty-one (96.9%) patients received R0 resection, two (6.3%) patients achieved pathological complete response, and 11 (34.4%) patients achieved pathological response. At the data cutoff date (September 30, 2021), the median event-free survival was 42.6 (95% CI, 16.2 to not reached) months, and the median overall survival was not reached. The most common grade 3 or 4 treatment-emergent adverse events were hypertension (9/32, 28.1%), thrombocytopenia (7/32, 21.9%), and neutropenia (5/32, 15.6%). Seven (21.9%) patients developed surgical complications, and the most common one was intra-abdominal abscess (4/32, 12.5%).
The concomitant use of apatinib, oxaliplatin, and capecitabine as neoadjuvant therapy showed promising efficacy and manageable safety profile in patients with locally advanced adenocarcinoma of the stomach or GEJ, and further phase 3 study is warranted.
This study was registered with ClinicalTrial.gov ( NCT03229096 ).
Chemoresistance is a main obstacle in gastric cancer (GC) treatment, but its molecular mechanism still needs to be elucidated. Here, we aim to reveal the underlying mechanisms of nanoparticle ...albumin-bound paclitaxel (nab-paclitaxel) resistance in GC.
We performed RNA sequencing (RNA-seq) on samples from patients who were resistant or sensitive to nab-paclitaxel, and identified Zinc Finger Protein 64 (ZFP64) as critical for nab-paclitaxel resistance in GC. CCK8, flow cytometry, TUNEL staining, sphere formation assays were performed to investigate the effects of ZFP64 in vitro, while subcutaneous tumor formation models were established in nude mice or humanized mice to evaluate the biological roles of ZFP64 in vivo. Chromatin immunoprecipitation sequencing (CHIP-seq) and double-luciferase reporter gene assay were conducted to reveal the underlying mechanism of ZFP64.
ZFP64 overexpression was linked with aggressive phenotypes, nab-paclitaxel resistance and served as an independent prognostic factor in GC. As a transcription factor, ZFP64 directly binds to Galectin-1 (GAL-1) promoter and promoted GAL-1 transcription, thus inducing stem-cell like phenotypes and immunosuppressive microenvironment in GC. Importantly, compared to treatment with nab-paclitaxel alone, nab-paclitaxel plus GAL-1 blockade significantly enhanced the anti-tumor effect in mouse models, particularly in humanized mice.
Our data support a pivotal role for ZFP64 in GC progression by simultaneously promoting cellular chemotherapy resistance and tumor immunosuppression. Treatment with the combination of nab-paclitaxel and a GAL-1 inhibitor might benefit a subgroup of GC patients.
A common clinicopathological factor except for T stage that could significantly influence the clinical outcome of advanced node-negative gastric cancer patients following radical gastrectomy was ...unknown. This study was designed to investigate the clinicopathological characteristics of these patients, and to evaluate the outcome indicators and improve the risk stratification.
A total of 195 patients harboring advanced gastric adenocarcinoma with no lymph node and distant metastases and following radical gastrectomy were retrospectively analyzed from the prospectively collected database of Zhongshan Hospital of Fudan University between 2006 and 2010.
The 3-year and 5-year overall survival rates of this study population were 85.0 and 69.6%. Factors influencing the overall survival were the degree of tumor differentiation, the depth of invasion and the number of lymph nodes resected (LN, cutoff = 18). Lymph node was recognized as an independent prognostic factor for overall survival of advanced node-negative gastric cancer patients, and the prognosis of the patients with greater number of lymph nodes resected (LN ≥ 18) was significantly better than those with lymph node < 18, and only the patients with T3/T4 stage could be significantly stratified by lymph node. Based on this condition, a new staging system named tumor-node-metastasis staging system for T3/T4 node-negative gastric cancer was constructed, which could have statistically different overall survival between subgroups.
Lymph node was an independent prognostic factor of patients with advanced node-negative gastric cancer, and retrieval of more than 18 lymph nodes should be warranted. In addition, these patients with lesser number of lymph nodes resected might need aggressive postoperative treatment and closer follow-up.
Although traditional treatments confer survival benefits to patients with gastric cancer (GC), many patients experience relapse soon after postoperative adjuvant therapy. Immune-related mechanisms ...play an important role in GC, and immunotherapeutic strategies are considered to be a promising direction for the treatment of GC. Thus, our study aimed to investigate the expression and prognostic significance of immune-related genes in GC.
Formalin-fixed, paraffin-embedded samples were collected from 48 resectable GC patients. The transcriptome data of the tumor immune microenvironment were assessed using an immuno-oncology 395-gene panel RNA sequencing platform. The prognostic value of the 395 genes was analyzed and validated in the KM plotter and GEPIA databases. The data from The Cancer Genome Atlas (TCGA, downloaded from UCSC Xena repository) and Tumor IMmune Estimation Resource (TIMER) were used to evaluate the correlations between prognostic factors and immune signatures.
Among the 395 genes, NOTCH3 was identified as a good prognostic factor for GC patients. Its prognostic value was also suggested in both our GC cohort from Zhongshan Hospital and the public databases (KM plotter and GEPIA database). Mechanistically, high NOTCH3 expression correlated with a lower infiltration of activated CD8
T cells and a higher infiltration of immunosuppressive cells including Tregs and M2 macrophages in the tumor microenvironment. Moreover, high NOTCH3 expression was accompanied by the increased expression of a series of immune checkpoint inhibitors, resulting in a dampened immune response. Interestingly, NOTCH3 expression had a negative association with well-documented predictive biomarkers of immune checkpoint blockade (ICB) immunotherapy, including tumor mutation burden (TMB), gene expression profiling (GEP) score and innate anti-PD-1 resistance (IPRES) signature.
These findings uncovered a new mechanism by which NOTCH3 participates in the immune tolerance of GC, implying the potential of NOTCH3 as a therapeutic target or predictive marker for GC patients.
The Neo-REGATTA study evaluated the effectiveness and safety of Docetaxel, oxaliplatin, and S-1 (DOS regimen) followed by radical resection vs. chemotherapy in advanced gastric adenocarcinoma ...patients with single non-curable factor.
This cohort study prospectively enrolled advanced gastric adenocarcinoma patients with single non-curable factor between November 2017 and June 2021. Patients without progression after four cycles of DOS were divided into resection group and chemotherapy group. The outcomes included overall survival (OS), progression-free survival (PFS) and safety. Effectiveness analysis was also performed by propensity score matching (PSM).
A total of 73 patients were enrolled and 13 patients were withdrawn due to disease progression after 4 cycles of DOS. Afterwards, 35 and 25 participants were in the resection and chemotherapy groups, respectively. After a median follow-up time of 30.0 months, the median PFS and OS were 9.0 months, and 18.0 months for the chemotherapy group, but not reached in the resection group. After PSM, 19 matched participants were in each group, and the median PFS and OS were longer in resection group than that in chemotherapy group. The most common grade 3 or 4 adverse events both in the resection group and chemotherapy groups were neutropenia (5.7%, 8.0%) and leukopenia (5.7%, 8.0%).
Radical resection might provide survival benefit compared with continuous chemotherapy alone in advanced gastric adenocarcinoma patients who had a disease control after DOS, with a good safety profile.
The study protocol was registered on ClinicalTrial.gov (NCT03001726, 23/12/2016).
With dichotomous etiology and pathogenesis, intestinal type and diffuse type gastric cancers vary in their clinical and molecular features to the point of representing distinct entities. However, the ...differences of tumor-infiltrating immune cells within the two types of gastric cancer have not been well researched. This study was aimed to evaluate the functional impact of Lauren classification on immune contexture in gastric cancer patients. Tumor tissues of gastric cancer patients from Zhongshan Hospital and gastric cancer data from The Cancer Genome Atlas (TCGA) cohort were analyzed. By immunohistochemistry and flow cytometry, we found that intratumoral CD8
+
T cells were more abundant but less functional in diffuse type as compared with those in intestinal type tumor tissues. Survival analysis indicated that CD8
+
T cells yielded favorable prognosis only in intestinal type patients other than diffuse type cancer patients. Moreover, such diffuse type-associated CD8
+
T cell dysfunction was featured by elevated expression of immunosuppressive factors including interleukin-10 (IL-10), transforming growth factor-β1 (TGF-β1) and indoleamine 2,3-dioxygenase 1 (IDO1). In summary, we found that the density, prognostic significance and functional status of intratumoral CD8
+
T cells varied with Lauren subtypes in gastric cancer. These results further indicated Lauren classification might be a potential therapeutic marker, and should be considered in therapeutic decisions, especially immunotherapeutic eligibility.
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