TGFß-Responsive Stromal Activation Occurs Early in Serrated Colorectal Carcinogenesis.

Activated TGFß signaling in the tumor microenvironment, which occurs independently of epithelial cancer cells, has emerged as a key driver of tumor progression in late-stage colorectal cancer (CRC). This study aimed to elucidate the contribution of TGFß-activated stroma to serrated carcinogenesis, representing approximately 25% of CRCs and often characterized by oncogenic BRAF mutations. We used a transcriptional signature developed based on TGFß-responsive, stroma-specific genes to infer TGFß-dependent stromal activation and conducted in silico analyses in 3 single-cell RNA-seq datasets from a total of 39 CRC samples and 12 bulk transcriptomic datasets consisting of 2014 CRC and 416 precursor samples, of which 33 were serrated lesions. Single-cell analyses validated that the signature was expressed specifically by stromal cells, effectively excluding transcriptional signals derived from epithelial cells. We found that the signature was upregulated during malignant transformation and cancer progression, and it was particularly enriched in CRCs with mutant BRAF compared to wild-type counterparts. Furthermore, across four independent precursor datasets, serrated lesions exhibited significantly higher levels of TGFß-responsive stromal activation compared to conventional adenomas. This large-scale analysis suggests that TGFß-dependent stromal activation occurs early in serrated carcinogenesis. Our study provides novel insights into the molecular mechanisms underlying CRC development via the serrated pathway.

Radiological Cutoff Values for Diagnosis of Lymph Node Metastasis in Colorectal Cancer With Multilevel Analysis.

Background/Aim: A cutoff value for lymph node diameter in colorectal cancer lymph node metastases has not been established. This prospective study aimed to investigate the direct association between swollen lymph nodes identified on preoperative computed tomography (CT) and pathological findings and proposed a cutoff value. Patients and Methods: We enrolled patients scheduled to undergo curative surgery with lymph node dissection for colorectal adenocarcinoma who underwent preoperative contrast-enhanced CT and had swollen lymph nodes ≥7 mm in diameter. Two gastrointestinal surgeons intraoperatively identified the target lymph nodes to assess the association between lymph node diameter and pathological findings. The diagnostic performance for lymph node metastasis was determined using multi-level logistic modelling. Results: A total of 109 patients were enrolled, and 225 swollen lymph nodes were pathologically evaluated. Using a cutoff value of ≥9 mm for the short diameter, the positive and negative predictive values, sensitivity, and specificity were 100.0% (99.6%-100.0%), 99.9% (99.1%-100.0%), 62.0% (45.6%-76.0%), and 84.9% (67.0%-94.0%), respectively. Conclusion: The cutoff value for improving the positive predictive value for the preoperative lymph node metastasis diagnosis in colorectal cancer patients should be at least 9 mm in diameter.

Evaluation of the prognostic impact of pathologic tumor regression grade on patients with colorectal cancer after preoperative chemoradiotherapy.

BACKGROUND: The prognostic value of the pathological response to preoperative chemoradiotherapy (CRT) in rectal cancer (RC) remains unknown. OBJECTIVES: We aimed to assess the predictive value of the response to CRT that was derived from an evaluation of the histological findings (whole-section vs. representative-section sampling) and attempted to determine an objective cut-off value for the tumor regression grade (TRG). METHODS: We examined the association of the TRG with the outcomes (recurrence-free survival [RFS] and overall survival [OS]) of 78 patients with RC. Patients with RC treated with preoperative CRT were divided into development (30 cases) and validation (48 cases) cohorts. The TRG was classified as grades I (Ia, Ib), II, and III. The cut-off value was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: The TRG determined from whole-section sampling versus representative-section sampling was more strongly correlated with patient survival. We found that in both cohorts, patients with a cut-off value of <73% had a poor prognosis. Finally, the cut-off value was found to be an independent predictive factor in both univariate and multivariate analysis. CONCLUSIONS: The TRG that was used to evaluate patients with RC who underwent preoperative CRT was an independent prognostic factor for outcome.

Biomarker-oriented chemo-immunotherapy for advanced gastric cancer.

The biomarker-oriented chemo-immunotherapy is useful and promising in the development of new anticancer agents, since the responders can be enriched by selecting patients with biomarkers. Compared to colorectal and lung cancers, the development of biomarker-driven molecular-targeted therapeutics for gastric cancers has been straggled. However, several new biomarkers in gastric cancers have been discovered and clinical trials in enrichment design with certain biomarkers have been conducted. Therefore, there are currently several treatment options to treat gastric cancer patients based on individual biomarker-oriented strategies. In the present review, we describe the useful biomarkers in gastric cancer, with focusing on HER2, PD-L1, and Claudin18.2, in relation to their clinical significance and associated targeted agents.

The real-world data of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer: a multi-institutional cohort study.

BACKGROUND: The real-world efficacy, feasibility, and prognostic factors of immune-checkpoint inhibitor combination therapy for unresectable or metastatic esophageal cancer are not fully established. METHODS: This multi-institutional retrospective cohort study evaluated 71 consecutive patients treated with immune-checkpoint inhibitor combination therapy for esophageal cancer between March 2021 and December 2022. We assessed tumor response, safety, and long-term survival. RESULTS: In patients with measurable lesions, the response rate was 58%, and the disease control rate for all enrolled patients was 80%. Five patients (7.0%) underwent successful conversion surgery. Grade 3 or higher immune-related adverse events occurred in 13% of patients, and one patient (1.4%) died due to cholangitis. Median progression-free survival was 9.7 (95% confidence interval: 6.5-not reached). C-reactive protein levels and performance status were identified as significant predictors of progression-free survival through Cox proportional hazards analysis. CONCLUSIONS: Immune-checkpoint inhibitor combination therapy for esophageal cancer demonstrated comparable tumor response, safety, and long-term survival to previous randomized clinical trials. Patients with good performance status and low C-reactive protein levels may be suitable candidates for this treatment.

Proton beam reirradiation for locally recurrent rectal cancer patients with prior pelvic irradiation.

The aim of the present study was to report the feasibility of proton beam reirradiation for patients with locally recurrent rectal cancer (LRRC) with prior pelvic irradiation. The study population included patients who were treated with proton beam therapy (PBT) for LRRC between 2008 and December 2019 in our institution. Those who had a history of distant metastases of LRRC, with or without treatment, before reirradiation, were excluded. Overall survival (OS), progression-free survival (PFS) and local control (LC) were estimated using the Kaplan-Meier method. Ten patients were included in the present study. The median follow-up period was 28.7 months, and the median total dose of prior radiotherapy (RT) was 50 Gy (range, 30 Gy-74.8 Gy). The median time from prior RT to reirradiation was 31.5 months (range, 8.1-96.6 months), and the median reirradiation dose was 72 Gy (relative biological effectiveness) (range, 56-77 Gy). The 1-year/2-year OS, PFS and LC rates were 100%/60.0%, 20.0%/10.0% and 70.0%/58.3%, respectively, with a median survival time of 26.0 months. Seven patients developed a Grade 1 acute radiation dermatitis, and no Grade ≥ 2 acute toxicity was recorded. Grade ≥ 3 late toxicity was recorded in only one patient, who had developed a colostomy due to radiation-related intestinal bleeding. Reirradiation using PBT for LRRC patients who had previously undergone pelvic irradiation was feasible. However, the indications for PBT reirradiation for LRRC patients need to be considered carefully due to the risk of severe late GI toxicity.

[365 Days in Newly Opened Cancer Treatment Center in Core Hospital of Mountainous Area].

The declining birthrate and aging population is one of the social issues in mountainous area in Japan. One regional core hospital at Aizu area in Fukushima prefecture opened cancer treatment center in these area in July, 2022. A high-performance radiation therapy system was newly installed and operated with the staff of Fukushima Medical University, and several supportive therapy for cancer chemotherapy including appearance care became possible in the center. The patients living in Aizu area can receive advanced treatments including radiation therapy without moving to long-distant bigger cities now. We report multiple preparations and several trials that we have made during one year since the opening of the center.

The tumor cell-intrinsic cGAS-STING pathway is associated with the high density of CD8+ T cells after chemotherapy in esophageal squamous cell carcinoma.

BACKGROUND: Chemotherapy has the potential to induce CD8+ T-cell infiltration in the tumor microenvironment (TME) and activate the anti-tumor immune response in several cancers including esophageal squamous cell carcinoma (ESCC). The tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been known as a critical component for regulating immune cell activation in the TME. However, its effect on the infiltration of immune cells induced by chemotherapy in the ESCC TME has not been investigated. METHODS: We examined the effect of the tumor-cell intrinsic cGAS-STING pathway on the infiltration of CD8+ T cells induced by chemotherapy in ESCC using ESCC cell lines and surgically resected ESCC specimens from patients who received neoadjuvant chemotherapy (NAC). RESULTS: We found that chemotherapeutic agents, including 5-fluorouracil (5-FU) and cisplatin (CDDP), activated the cGAS-STING pathway, consequently inducing the expression of type I interferon and T-cell-attracting chemokines in ESCC cells. Moreover, the tumor cell-intrinsic expression of cGAS-STING was significantly and positively associated with the density of CD8+ T cells in ESCC after NAC. However, the tumor cell-intrinsic expression of cGAS-STING did not significantly impact clinical outcomes in patients with ESCC after NAC. CONCLUSION: Our findings suggest that the tumor cell-intrinsic cGAS-STING pathway might contribute to chemotherapy-induced immune cell activation in the ESCC TME.

Recurrence-free survival as a surrogate endpoint for overall survival after neoadjuvant chemotherapy and surgery for oesophageal squamous cell carcinoma.

BACKGROUND: Overall survival is considered as one of the most important endpoints of treatment efficacy but often requires long follow-up. This study aimed to determine the validity of recurrence-free survival as a surrogate endpoint for overall survival in patients with surgically resectable advanced oesophageal squamous cell carcinoma (OSCC). METHODS: Patients with OSCC who received neoadjuvant cisplatin and 5-fluorouracil, or docetaxel, cisplatin and 5-fluorouracil, at 58 Japanese oesophageal centres certified by the Japan Esophageal Society were reviewed retrospectively. The correlation between recurrence-free and overall survival was assessed using Kendall's τ. RESULTS: The study included 3154 patients. The 5-year overall and recurrence-free survival rates were 56.6 and 47.7% respectively. The primary analysis revealed a strong correlation between recurrence-free and overall survival (Kendall's τ 0.797, 95% c.i. 0.782 to 0.812) at the individual level. Subgroup analysis showed a positive relationship between a more favourable pathological response to neoadjuvant chemotherapy and a higher τ value. In the meta-regression model, the adjusted R2 value at the institutional level was 100 (95% c.i. 40.2 to 100)%. The surrogate threshold effect was 0.703. CONCLUSION: There was a strong correlation between recurrence-free and overall survival in patients with surgically resectable OSCC who underwent neoadjuvant chemotherapy, and this was more pronounced in patients with a better response to neoadjuvant chemotherapy.

Endosomal protein expression of γ1-adaptin is associated with tumor growth activity and relapse-free survival in breast cancer.

BACKGROUND: γ1-Adaptin is a subunit of adaptor protein complex-1 (AP-1), which regulates intracellular transport between the trans-Golgi network (TGN) and endosomes. Since expression levels of AP-1 subunits have been reported to be associated with cell proliferation and cancer malignancy, we investigated the relationships between the immunohistochemical expression of γ1-adaptin and both clinicopathological factors and relapse-free survival (RFS) in breast cancer tissue. MATERIALS AND METHODS: SK-BR-3 cell line depleted of γ1-adaptin was used for cell proliferation, migration, and invasion assay. Intracellular localization of γ1-adaptin was examined with immunohistochemistry (IHC) using an antibody against γ1-adaptin, and with double immunohistofluorescence (IHF) microscopy using markers for the TGN and endosome. γ1-Adaptin intensities in IHC samples from 199 primary breast cancer patients were quantified and assessed in relation to clinicopathological factors and RFS. RESULTS: Cell growth, migration, and invasion of SK-BR-3 cells were significantly suppressed by the depletion of γ1-adaptin. Although the staining patterns in the cancer tissues varied among cases by IHC, double IHF demonstrated that γ1-adaptin was mainly localized in EEA1-positive endosomes, but not in the TGN. γ1-Adaptin intensity was significantly higher in the tumor regions than in non-tumor regions. It was also higher in patients with Ki-67 (high), ER (-), PgR (-), and HER2 (+). Among subtypes of breast cancer, γ1-adaptin intensity was higher in HER2 than in luminal A or luminal B. The results of the survival analysis indicated that high γ1-adaptin intensity was significantly associated with worse RFS, and this association was also observed in group with ER (+), PgR (+), HER2 (-), Ki-67 (high), or luminal B. In addition, the Cox proportional hazards model showed that high γ1-adaptin intensity was an independent prognostic factor. CONCLUSION: These results suggest that the endosomal expression of γ1-adaptin is positively correlated with breast cancer malignancy and could be a novel prognostic marker.

Combination of oligo-fractionated irradiation with nivolumab can induce immune modulation in gastric cancer.

BACKGROUND: Tumor-associated antigen (TAA)-specific CD8(+) T cells are essential for nivolumab therapy, and irradiation has been reported to have the potential to generate and activate TAA-specific CD8(+) T cells. However, mechanistic insights of T-cell response during combinatorial immunotherapy using radiotherapy and nivolumab are still largely unknown. METHODS: Twenty patients included in this study were registered in the CIRCUIT trial (ClinicalTrials.gov, NCT03453164). All patients had multiple distant metastases and were intolerance or had progressed after primary and secondary chemotherapy without any immune checkpoint inhibitor. In the CIRCUIT trial, eligible patients were treated with a total of 22.5 Gy/5 fractions/5 days of radiotherapy to the largest or symptomatic lesion prior to receiving nivolumab every 2 weeks. In these 20 patients, T-cell responses during the combinatorial immunotherapy were monitored longitudinally by high-dimensional flow cytometry-based, multiplexed major histocompatibility complex multimer analysis using a total of 46 TAAs and 10 virus epitopes, repertoire analysis of T-cell receptor ß-chain (TCRß), together with circulating tumor DNA analysis to evaluate tumor mutational burden (TMB). RESULTS: Although most TAA-specific CD8(+) T cells could be tracked longitudinally, several TAA-specific CD8(+) T cells were detected de novo after irradiation, but viral-specific CD8(+) T cells did not show obvious changes during treatment, indicating potential irradiation-driven antigen spreading. Irradiation was associated with phenotypical changes of TAA-specific CD8(+) T cells towards higher expression of killer cell lectin-like receptor subfamily G, member 1, human leukocyte antigen D-related antigen, T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, CD160, and CD45RO together with lower expression of CD27 and CD127. Of importance, TAA-specific CD8(+) T cells in non-progressors frequently showed a phenotype of CD45RO(+)CD27(+)CD127(+) central memory T cells compared with those in progressors. TCRß clonality (inverted Pielou's evenness) increased and TCRß diversity (Pielou's evenness and Diversity Evenness score) decreased during treatment in progressors (p=0.029, p=0.029, p=0.012, respectively). TMB score was significantly lower in non-progressors after irradiation (p=0.023). CONCLUSION: Oligo-fractionated irradiation induces an immune-modulating effect with potential antigen spreading and the combination of radiotherapy and nivolumab may be effective in a subset of patients with gastric cancer.

Prognostic impact and survival outcomes of colon perforation in patients with metastatic colorectal cancer: a multicenter retrospective cohort study.

BACKGROUND: Colon perforation caused by colorectal cancer (CRC) is a fatal condition requiring emergency intervention. For patients with metastatic lesions, surgeons face difficult decisions regarding whether to resect the primary and metastatic lesions. Moreover, there is currently no established treatment strategy for these patients. This study aimed to investigate the clinical practice and long-term outcomes of patients with metastatic CRC diagnosed with the onset of colon perforation. METHODS: We performed a population-based multicenter cohort study. Consecutive patients diagnosed with stage IV CRC between 2008 and 2015 at all designated cancer hospitals in Fukushima Prefecture, Japan, were enrolled in this study. We evaluated the impact of colon perforation on the survival outcomes of patients with metastatic CRC. The main outcome was the adjusted hazard ratio (aHR) of perforation for overall survival (OS). Survival time and HRs were estimated using Kaplan‒Meier and Cox proportional regression analyses. RESULTS: A total of 1258 patients were enrolled (perforation: n = 46; non-perforation: n = 1212). All but one of the patients with perforation underwent primary resection or colostomy and 25 cases were able to receive chemotherapy. The median OS for the perforation and non-perforation groups was 19.0 and 20.0 months, respectively (p = 0.96). Moreover, perforation was not an independent prognostic factor (aHR: 0.99; 95% confidence interval: 0.61-1.28). CONCLUSIONS: In metastatic CRC, perforation is not necessarily a poor prognostic factor. Patients with perforation who undergo primary tumor resection or colostomy and prompt initiation of systemic chemotherapy might be expected to have a survival time similar to that of patients with non-perforated colon.

Outcomes of patients with esophageal squamous cell carcinoma who achieved a pathological complete response in the primary lesion by neoadjuvant treatment: a Japanese nationwide cohort study.

BACKGROUND: Minimal data was reported regarding the characteristics, risks of lymph node metastasis, and prognostic factors in esophageal cancer patients who achieved remarkable response in the primary lesion to neoadjuvant treatment (NAT). METHODS: This study evaluated the nationwide data of esophageal squamous cell carcinoma (ESCC) patients who underwent surgery following NAT in Japan. Of 4484 patients, 300 (6.7%) had ypT0 following NAT and curative esophagectomy. Factors associated with lymph node metastasis and prognosis were analyzed. RESULTS: Neoadjuvant chemotherapy (NAC) and neoadjuvant chemoradiotherapy (NACRT) were administered in 260 (86.2%) and 40 (13.8%) patients, respectively. Pathologically, 72 (24.0%) had lymph node metastasis (residual nodal disease; RND), and pretherapeutic lymph node metastasis was the independent risk factor for RND (odd ratio [OR]: 3.21; 95% confidence interval [CI]: 1.44-8.20; P = 0.008). The 5-year overall and relapse-free survivals were significantly longer in patients with pathological complete response (pCR) than in those with RND (both P < 0.001). Pretherapeutic cT3 or T4a tumors (hazard ratio [HR]: 1.71; 95% CI: 1.02-2.88; P = 0.043), RND (HR: 3.30; 95% CI: 1.98-5.50; P < 0.001), and operative blood loss (Liter, HR: 1.53; 95% CI: 1.07-2.19; P = 0.021) were independent risk factors affecting relapse-free survival in multivariable analysis. CONCLUSIONS: Of patients with ypT0 after NAT, 24.0% had RND, and pretherapeutic lymph node metastasis was the risk factor. In addition, pretherapeutic cT3, or T4a tumors, RND, and operative blood loss were the poor prognosticators in patients with ypT0 after NAT.

[Remodeling of the Tumor Microenvironment by Radiotherapy through the cGAS-STING Pathway in Esophageal Squamous Cell Carcinoma].

It has been reported that tumor cell-intrinsic cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING) pathway is essential for radiotherapy(RT)-induced activation of anti-tumor immune responses. However, its role in the RT- induced remodeling of the tumor microenvironment(TME)in esophageal squamous cell carcinoma(ESCC), is largely unknown. In this study, we found that the tumor cell-intrinsic cGAS-STING pathway is a critical component for RT-induced activation of immune cells in the TME through the induction of type Ⅰ interferon and C-X-C motif chemokine ligand 10 in tumor cells in ESCC. However, at the same time, the tumor cell-intrinsic cGAS-STING pathway is also involved in RT-triggered infiltration and polarization of immunosuppressive CD163+ tumor-associated macrophages (TAM) through the induction of interleukin 34 (IL-34) in tumor cells in ESCC. Our findings suggest that targeting IL-34 to impede the infiltration and polarization of CD163+ TAM could potentially enhance the efficacy of RT-induced immune cell activation in ESCC TME.

TIM-3 Expression and M2 Polarization of Macrophages in the TGFß-Activated Tumor Microenvironment in Colorectal Cancer.

TGFß signaling in the tumor microenvironment (TME) drives immune evasion and is a negative predictor of immune checkpoint inhibitor (ICI) efficacy in colorectal cancer (CRC). TIM-3, an inhibitory receptor implicated in anti-tumor immune responses and ICI resistance, has emerged as an immunotherapeutic target. This study investigated TIM-3, M2 macrophages and the TGFß-activated TME, in association with microsatellite instability (MSI) status and consensus molecular subtypes (CMSs). Transcriptomic cohorts of CRC tissues, organoids and xenografts were examined (n = 2240). TIM-3 and a TGFß-inducible stromal protein, VCAN, were evaluated in CRC specimens using immunohistochemistry (n = 45). TIM-3 expression on monocytes and generated M2 macrophages was examined by flow cytometry. We found that the expression of HAVCR2 (TIM-3) significantly correlated with the transcriptional signatures of TGFß, TGFß-dependent stromal activation and M2 macrophage, each of which were co-upregulated in CMS4, CMS1 and MSI CRCs across all datasets. Tumor-infiltrating TIM-3+ immune cells accumulated in TGFß-responsive cancer stroma. TIM-3 was increased on M2-polarized macrophages, and on monocytes in response to TGFß treatment. In conclusion, we identified a close association between TIM-3 and M2-like polarization of macrophages in the TGFß-rich TME. Our findings provide new insights into personalized immunotherapeutic strategies based on the TME for CRCs.

[The Potential of a Novel Therapeutic Strategy for Colorectal Cancer Targeting the cGAS-STING Pathway].

The cyclic GMP-AMP synthase(cGAS)-stimulator of interferon genes(STING)pathway is one of the important intracellular signaling pathways responsible for the recognition of exogenous DNA and subsequent induction of type Ⅰ interferon responses. Interestingly, in recent years, the importance of the cGAS-STING pathway in promoting anti-tumor immune responses has been highlighted. Decreased expression of cGAS-STING in tumor cells was reported in various cancers, including colorectal cancer(CRC), and it has been found to be involved in inhibiting the anti-tumor immune responses. In our recent investigation, we specifically examined the impact of tumor cell-intrinsic cGAS-STING pathway on the activation of immune cells within the CRC tumor microenvironment, focusing on mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H)and mismatch repair proficient/microsatellite stable(pMMR/MSS)CRCs. We revealed that cGAS-STING expression in tumor cells was decreased in pMMR/MSS CRC compared to dMMR/MSI-H CRC, which correlated with the decreased infiltration of cytotoxic T cells. Here, we discuss the possibility of a novel therapeutic strategy for CRC targeting the tumor cell-intrinsic cGAS-STING pathway based on the findings from recent studies.

Immunological Responses Associated With Neoadjuvant Therapy in the Tumor Microenvironment of Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIM: Development of multidisciplinary therapies including immune checkpoint inhibitors for esophageal squamous cell carcinoma (ESCC) requires a clear understanding of immunological responses induced by chemotherapy with/without radiotherapy in the tumor microenvironment. PATIENTS AND METHODS: This is a retrospective analysis of paired pretreatment biopsy samples and surgically resected tumor samples of 49 patients who underwent radical surgery for ESCC with/without neoadjuvant therapy at Fukushima Medical University Hospital. The cohort included 30 patients treated with neoadjuvant chemotherapy (NAC), 11 treated with neoadjuvant chemoradiotherapy (NACRT), and eight who underwent surgery alone and did not receive neoadjuvant antitumor therapy. Chemotherapy included fluoropyrimidine- and platinum-based agents in all treated patients, and radiotherapy included 40 or 42 Gy administered in 20 or 21 fractions. Expression of CD8, human leukocyte antigen (HLA) class I-ABC, PD-L1, PD-L2, CEACAM-1, LSECtin, and p-STAT1, were determined using immunohistochemistry. RESULTS: The frequency of tumor-infiltrating CD8+ T cells was significantly increased by NAC (p<0.05), and the expression of HLA class I-ABC on tumor cells was significantly increased by NAC and NACRT (p<0.05). Furthermore, the ESCC cells expressed PD-L1, PD-L2, and CEACAM-1, whereas the expression of PD-L1 on ESCC cells was significantly correlated with the expression of p-STAT1 in ESCC cells (p<0.05). CONCLUSION: NAC and NACRT induced both positive and negative immunological responses in patients with ESCC. These results may be a part of basis for multidisciplinary therapy including immune checkpoint inhibitors for patients with advanced ESCC.

Down-regulation of stimulator of interferon genes (STING) expression and CD8+ T-cell infiltration depending on HER2 heterogeneity in HER2-positive gastric cancer.

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.

Phase I/II clinical trial of nivolumab in combination with oligo-fractionated irradiation for unresectable advanced or recurrent gastric cancer.

BACKGROUND: Although immune checkpoint inhibitors (ICI) targeting for PD-1 axis is a promising approach for advanced gastric cancer (GC) patients, the response rate is still limited. Induction of synergistic effect of irradiation with ICI targeting for the PD-1 axis can be an attractive strategy. The aim of this study was to assess the effect of the combination of irradiation with anti-PD-1 therapy for advanced GC. METHODS: We conducted a single-arm, phase I/II trial in GC patients treated with a combination of nivolumab and oligo-fractionated irradiation (22.5 Gy/5 fractions/5 days) (NCT03453164). Eligible patients (n = 40) had unresectable advanced or recurrent GC which progressed after primary and secondary chemotherapy with more than one lesion. The primary endpoint is the disease control rate (DCR) of non-irradiated target lesions and the secondary endpoints are the median survival time (MST), safety, and DCR of irradiated lesions. RESULTS: We observe that the DCR for the non-irradiated target as the abscopal effect is 22.5% (90% confidence interval (CI), 12.3-36.0), and the DCR for the irradiated lesion is 40.0% (90% CI, 26.9-54.2). The median survival time is 230 days (95% CI, 157-330), and grade 3 and higher adverse events (AEs) are observed in 16 patients (39 %) with no obvious additional AEs when adding irradiation. CONCLUSIONS: The present study suggests that the combination of nivolumab with oligo-fractionated irradiation has the potential to induce a promising anti-tumor effect for advanced GC.

Immunotherapy is a type of treatment that triggers the immune system to kill cancers. Combining immunotherapy with radiotherapy may enhance its effects. We evaluated this in a clinical trial in which we treated patients with advanced or recurrent cancers of the stomach (gastric cancer) with a combination of immunotherapy and radiotherapy. The combination was able to control disease in a subset of patients and was safe, with no obvious additional adverse effects when adding radiotherapy. The median survival time­at which point half of the patients treated are still alive­was 230 days. While these results are promising, larger, more rigorous studies are needed to determine whether this combination therapy is better than alternative approaches to treating advanced or recurrent gastric cancers.

A Potential Biomarker of Dynamic Change in Peripheral CD45RA-CD27+CD127+ Central Memory T Cells for Anti-PD-1 Therapy in Patients with Esophageal Squamous Cell Carcinoma.

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 (TCM) were significantly decreased during the course of NT in the progressive disease group. Taken together, the alteration in frequency of CD45RA-CD27+CD127+ TCM during NT may be a biomarker to predict its therapeutic response in ESCC patients.