Fibroblast activation protein-targeted near-infrared photoimmunotherapy depletes immunosuppressive cancer-associated fibroblasts and remodels local tumor immunity.

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage. METHODS: In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP+ CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity. RESULTS: FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8+ tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8+ TILs compared with non-treated tumors, suggesting enhanced antitumor immunity. CONCLUSIONS: Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF+ tumors.

Overcoming cancer-associated fibroblast-induced immunosuppression by anti-interleukin-6 receptor antibody.

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment and play a central role in tumor progression. Previously, we reported that CAFs might induce tumor immunosuppression via interleukin-6 (IL-6) and promote tumor progression by blocking local IL-6 in the tumor microenvironment with neutralizing antibody. Here, we explore whether an anti-IL-6 receptor antibody could be used as systemic therapy to treat cancer, and further investigate the mechanisms by which IL-6 induces tumor immunosuppression. In clinical samples, IL-6 expression was significantly correlated with α-smooth muscle actin expression, and high IL-6 cases showed tumor immunosuppression. Multivariate analysis showed that IL-6 expression was an independent prognostic factor. In vitro, IL-6 contributed to cell proliferation and differentiation into CAFs. Moreover, IL-6 increased hypoxia-inducible factor 1α (HIF1α) expression and induced tumor immunosuppression by enhancing glucose uptake by cancer cells and competing for glucose with immune cells. MR16-1, a rodent analog of anti-IL-6 receptor antibody, overcame CAF-induced immunosuppression and suppressed tumor progression in immunocompetent murine cancer models by regulating HIF1α activation in vivo. The anti-IL-6 receptor antibody could be systemically employed to overcome tumor immunosuppression and improve patient survival with various cancers. Furthermore, the tumor immunosuppression was suggested to be induced by IL-6 via HIF1α activation.

PD-L1-expressing cancer-associated fibroblasts induce tumor immunosuppression and contribute to poor clinical outcome in esophageal cancer.

The programmed cell death 1 protein (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays a crucial role in tumor immunosuppression, while the cancer-associated fibroblasts (CAFs) have various tumor-promoting functions. To determine the advantage of immunotherapy, the relationship between the cancer cells and the CAFs was evaluated in terms of the PD-1/PD-L1 axis. Overall, 140 cases of esophageal cancer underwent an immunohistochemical analysis of the PD-L1 expression and its association with the expression of the α smooth muscle actin, fibroblast activation protein, CD8, and forkhead box P3 (FoxP3) positive cells. The relationship between the cancer cells and the CAFs was evaluated in vitro, and the effect of the anti-PD-L1 antibody was evaluated using a syngeneic mouse model. A survival analysis showed that the PD-L1+ CAF group had worse survival than the PD-L1- group. In vitro and in vivo, direct interaction between the cancer cells and the CAFs showed a mutually upregulated PD-L1 expression. In vivo, the anti-PD-L1 antibody increased the number of dead CAFs and cancer cells, resulting in increased CD8+ T cells and decreased FoxP3+ regulatory T cells. We demonstrated that the PD-L1-expressing CAFs lead to poor outcomes in patients with esophageal cancer. The cancer cells and the CAFs mutually enhanced the PD-L1 expression and induced tumor immunosuppression. Therefore, the PD-L1-expressing CAFs may be good targets for cancer therapy, inhibiting tumor progression and improving host tumor immunity.

[Three Cases of Intrathecal Chemotherapy with Ventricular Catheter for the Treatment of Leptomeningeal Metastasis from Breast Cancer].

Leptomeningeal metastasis(LM)is a rare complication in patients with breast cancer. We report 3 cases of LMs in patients with breast cancer who were treated with intrathecal methotrexate via an Ommaya reservoir. In 2 patients, a significant neurological improvement was observed, whereas in 1 patient there was no response. The overall survivals for the patients who experienced improvements were 22 and 9 months. Although we have no evidence for the efficacy of intrathecal chemotherapy for LMs in patients with breast cancer, its effects for some patients could be promising, after reservoir management and drug selection establishment.

[Local Recurrence of Rectal Cancer under Perineal Skin after Abdominoperineal Resection].

A woman in her early 50s underwent abdominoperineal resection with left lateral lymph node resection for advanced rectal cancer. The pathological diagnosis was RC, RbP, well-differentiated, type 5, 65×47mm, pT3(A), pN0(0/40), M0, pStage Ⅱ. The local recurrence discovered under the perineal skin 2 months later was treated by resecting the tumor and both inguinal lymph nodes. Adjuvant chemotherapy containing UFT plus LV was also initiated for 6 months. She remains free of recurrence 1 year after resection of the local recurrence.

[Assessment of Short-Term Outcomes of Laparoscopic-Assisted Distal Gastrectomy in Elderly Patients Using Comorbidities as Predictive Factors].

Laparoscopic-assisted distal gastrectomy(LADG)is a recently developed minimally invasive surgery for management of early gastric cancer. We describe short-term results obtained from a retrospective study of LADG, performed in elderly patients, using comorbidities as predictive factors. We studied 160 patients diagnosed with gastric cancer who underwent LADG between January 2005 and October 2016. We compared 48 patients, aged≥75 years(elder group), with 112 patients, aged <75 years(non-elder group), who underwent LADG. Preoperative physical status was assessed using the American Society of Anesthesiologists physical status(ASA-PS)score, Charlson comorbidity index(CCI), and the prognostic nutritional index (PNI). Demographics of patients, primarily, sex, tumor lesion, and histology did not significantly differ between the groups. However, the mean ASA-PS score and CCI were significantly higher, and the PNI was significantly lower in the elder group. Surgical duration, volume of blood loss, lymph node clearance, and length of postoperative hospital stay did not significantly differ between the groups. Cardiorespiratory and surgical complications developed in 2(4.2%)and 3(2.7%), and in 5(10%) and 12(11%)patients in the elder and non-elder groups, respectively. However, the rates of intra and postoperative complications were not significantly different between them. LADG can be considered a safe and effective minimally invasive surgical procedure for management of early gastric cancer in elderly patients.

[Case Report of Long-Term Survival for Stage IV Advanced Sigmoid Colon Cancer with Para-Aortic Nodes by R0 Resection and Chemotherapy].

The patient was a man in his early 30s. He underwent sigmoidectomy with D3+ #216 for advanced sigmoid colon cancer with metastatic para-aortic lymph nodes. The pathological diagnosis was colon cancer(S), type 2, moderately differentiated, pT4a(SE), pN3(19/33), pM1a(LYM), pStage IV , KRAS wild-type, EGFR(+). He received FOLFOX plus bevacizumab(Bmab) as adjuvant chemotherapy. One year postoperatively, he experienced recurrence as multiple lung metastases. FOLFIRI plus panitumumab, SOX plus Bmab, CapeOX, nivolumab and FOLFIRI plus ramucirumab were then administered. The patient has survived for 4 years and 11 months from operation.

Ten Cases of Colovesical Fistula due to Sigmoid Diverticulitis.

Colovesical fistula (CVF) resulting from colon diverticulosis is a comparatively rare disease, and neither the diagnosis nor treatment has been established. Our experience with CVF due to sigmoid diverticulitis over a 9-year period was reviewed to clarify the clinical presentation and diagnostic confirmation. Ten patients with CVF were identified in this period, and chief complaints, laboratory findings, presenting symptoms, diagnostic investigations, and subsequent treatments were reviewed. Preoperative urinalysis showing bacteriuria (100%) was the most common presentation, followed by fecaluria (40%), abdominal pain (40%), pneumaturia (30%), hematuria (30%), pain on urination (30%), pollakiuria (10%), and dysuria (10%). The abilities of various preoperative investigations to identify CVF were: computed tomography (CT), 88.9%; magnetic resonance imaging, 40%; cystoscopy, 30%, and gastrografin irrigoscopy, 22.2%. Colonoscopy (0%) was not diagnostic. Bowel resection was performed in nine of ten patients. When inflammation was intense, covering ileostomy was performed, and an omental plasty was placed between the bowel anastomosis and bladder. When CVF is suspected, we recommend CT followed by colonoscopy and cystoscopy as a first-line investigation to rule out malignancy as a cause. Other modalities should only be used if the diagnosis is in doubt or additional information is needed to plan operative management. Primary colic anastomosis appears to be safely performed by applying omental plasty and covering ileostomy.

Near-infrared Photoimmunotherapy Targeting Cancer-Associated Fibroblasts in Patient-Derived Xenografts Using a Humanized Anti-Fibroblast Activation Protein Antibody.

Esophageal cancer remains a highly aggressive malignancy with a poor prognosis, despite ongoing advancements in treatments such as immunotherapy. The tumor microenvironment, particularly cancer-associated fibroblasts (CAF), plays a crucial role in driving the aggressiveness of esophageal cancer. In a previous study utilizing human-derived xenograft models, we successfully developed a novel cancer treatment that targeted CAFs with near-infrared photoimmunotherapy (NIR-PIT), as an adjuvant therapy. In this study, we sought to translate our findings toward clinical practice by employing patient-derived xenograft (PDX) models and utilizing humanized mAbs, specifically sibrotuzumab, which is an antihuman fibroblast activation protein (FAP) Ab and already being investigated in clinical trials as monotherapy. PDX models derived from patients with esophageal cancer were effectively established, preserving the expression of key biomarkers such as EGFR and FAP, as observed in primary tumors. The application of FAP-targeted NIR-PIT using sibrotuzumab, conjugated with the photosensitizer IR700DX, exhibited precise binding and selective elimination of FAP-expressing fibroblasts in vitro. Notably, in our in vivo investigations using both cell line-derived xenograft and PDX models, FAP-targeted NIR-PIT led to significant inhibition of tumor progression compared with control groups, all without inducing adverse events such as weight loss. Immunohistologic assessments revealed a substantial reduction in CAFs exclusively within the tumor microenvironment of both models, further supporting the efficacy of our approach. Thus, our study demonstrates the potential of CAF-targeted NIR-PIT employing sibrotuzumab as a promising therapeutic avenue for the clinical treatment of patients with esophageal cancer.

Dual-targeted near-infrared photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in the tumor microenvironment.

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment.