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.

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.

[A Case of Mixed Hepatocellular and Primary Hepatic Neuroendocrine Carcinomas with Remnant Liver Recurrence and Rapid Exacerbation].

The patient was a 77-year-old man with a 4.0 cm hepatictumor in hepaticsegment 4. Plain computed tomography(CT) showed the tumor with low density. On dynamicexamination, the tumor showed heterogeneous enhancement during the arterial phase. Magneticresonanc e imaging showed the tumor as a low intensity area in the hepatobiliary phase in hepatic segments 4, 6, and 8. A month later, CT showed an enlarged tumor in segment 4 measuring 7.0 cm. We diagnosed the tumor as primary liver cancer and suspected it to be hepatocellular carcinoma(HCC)preoperatively. We performed extended medial segmentectomy and partial hepatectomy of segment 6. The histopathological diagnosis was mixed HCC and primary hepatic neuroendocrine carcinoma(PHNEC). Three months after hepatectomy, the patient died of multiple intrahepatic recurrences. In most of the reported cases of mixed HCC and PHNEC, only the PHNEC component has been detected in the biopsy of the metastatic lesions. This fact might suggest that PHNEC has a higher proliferative activity and malignant potential than HCC. Standard treatment for mixed HCC and PHNEC is unclear; therefore, development of multidisciplinary treatment strategies combining surgical treatment and systemic chemotherapy is required.

[A case of appendix cancer treated as cancer of unknown primary origin].

A 57-year-old man initially presented with chief complaints of abdominal distension and anorexia. Positron emission tomography- computed tomography (PET-CT) scan showed ascites and multiple peritoneal metastases with abnormal uptake of fluorodeoxyglucose (FDG). The patient underwent endoscopy, biopsy, and cytology and was diagnosed with adenocarcinoma of unknown primary origin. He was treated with systematic chemotherapy, including carboplatin/paclitaxel (CBDCA/ PTX) and gemcitabine regimens. However, progressive disease (PD) complicated by intestinal obstruction was indicated. He was referred to our department for management. We performed surgery to resolve the intestinal obstruction and confirm the diagnosis. Appendix cancer was diagnosed intraoperatively. He was administered a modified fluorouracil plus Leucovorin and oxaliplatin(mFOLFOX6) /panitumumab regimen following surgery. The tumor had a good response to treatment, and the primary lesion was resected. After resection , the tumor was controlled by systemic chemotherapy for six months. However, the patient unfortunately died owing to arrhythmia. Most patients with cancer of unknown primary origin have a very poor prognosis because it is difficult to select appropriate treatment. Laparotomy can be effective in making a definitive diagnosis, as in the case described here.

[A successful multimodality therapy for a case of recurrent rectal cancer with KRAS mutation].

A man in his 50s underwent high anterior resection for rectosigmoid cancer in January 2010. The primary tumor was diagnosed as a moderately differentiated adenocarcinoma with KRAS mutation, pStage III a. In May 2011, the patient had a recurrent lung tumor detected by computed tomography(CT); the tumor was resected using video-assisted thoracoscopic surgery. However, additional recurrent lung tumors arose, and radiofrequency ablation (RFA) was performed to treat these in February 2012. After RFA therapy, capecitabine was administered as adjuvant chemotherapy. Unfortunately, 10 months later, positron emission tomography (PET) /CT suggested a new recurrence in a left lateral lymph node. Although the pelvic lymph node was surgically removed immediately, a new lung recurrence was found on CT three months after the surgery. RFA was again used to treat this lung lesion. After the second RFA, the patient is doing well without any evidence of recurrence. We describe a case of recurrent rectal cancer successfully treated with multimodality therapy. The combination of appropriate local therapy with systemic chemotherapy is an essential strategy to treat advanced colorectal cancer, especially in patients with KRAS mutation when anti-EGFR antibodies are not effective.