ABSTRACT
BACKGROUND/AIM: Recent studies suggest that PD-L1 expression in immune cells, rather than tumor cells, plays a key role in tumor immunity. Trefoil factor family 1 (TFF1) is a secreted protein expressed mainly by the gastrointestinal epithelium and is related to the development of malignant disease. This study investigated the effects of TFF1 on tumor immunity in a xenograft mouse model of colorectal cancer (CRC). MATERIALS AND METHODS: MC38 cells were implanted in wild-type (WT) and TFF1KO mice, and the tumor micro-environment was investigated using immunohistochemistry. The circulating immune cells were analyzed using flow cytometry. RESULTS: Tumor growth was suppressed in TFF1KO mice. In the tumor microenvironment, CD8- and CD4-positive T cells and CD11c-positive dendritic cells (DCs) were frequently found in TFF1KO mice. When an immune checkpoint inhibitor was administered to these mice, almost half of the tumors in TFF1KO mice showed a complete response. The number of circulating PD-L1/DCs was markedly associated with tumor volume, with TFF1 deletion accelerating this effect and its injection decreasing it. These findings indicate that loss of TFF1 activates tumor immunity via frequent T-cell priming by DCs, and eventually suppresses tumor growth in CRC. In addition, the number of circulating PD-L1/DCs was identified as a predictive marker of checkpoint-inhibiting therapy efficacy. CONCLUSION: Loss of TFF1 resulted in accelerated immune response to colorectal cancer. Further studies are needed to investigate the precise mechanisms of TFF1 in immunotolerance and develop a novel TFF1-inhibiting immunotherapeutic strategy for CRC.
Subject(s)
Colorectal Neoplasms , Mice, Knockout , Trefoil Factor-1 , Tumor Microenvironment , Animals , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Trefoil Factor-1/genetics , Mice , Tumor Microenvironment/immunology , Humans , Dendritic Cells/immunology , Dendritic Cells/metabolism , Cell Line, Tumor , B7-H1 Antigen/genetics , B7-H1 Antigen/immunology , B7-H1 Antigen/metabolism , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/therapeutic use , Mice, Inbred C57BL , CD8-Positive T-Lymphocytes/immunologyABSTRACT
BACKGROUND: The carcinoembryonic antigen (CEA) "value" itself is often useless in patients with a normal CEA level at initial presentation and those with tumor-irrelevant elevated CEA. Although the unified marker using CEA has been desirable for recurrent tumor staging as well as for primary tumor staging, little is known concerning its relationship with the survival of patients with recurrent colorectal cancer in particular. METHODS: This retrospective historical study included patients who experienced disease relapse after curative surgery for stage I-III colorectal cancer between 2006 and 2018. A total of 129 patients with recurrent disease after curative surgery for colorectal cancer were included. We focused on the CEA "ratio" (CEA-R: the ratio of the CEA level at the time of recurrence to that measured 3 months before recurrence) and aimed to evaluate the correlation between CEA-R and survival in recurrent colorectal cancer. RESULTS: Patients with a high CEA-R (≥ 2) exhibited significantly worse 2 year survival than those with a low CEA-R (< 2) (88.1% vs. 44.9%, P < 0.001), irrespective of the CEA value before primary resection. Multivariate analyses demonstrated that the CEA-R (HR; 3.270, 95% CI 1.646-6.497, P = 0.001) was a significant prognostic factor. CONCLUSION: The CEA-R is a potential marker stratifying the survival of patients with disease relapse who exhibit aggressive biology at recurrent disease foci. As a novel marker, the CEA-R would serve as a clinical guide for tailoring treatment strategies at the time of disease relapse in patients with colorectal cancer.
Subject(s)
Carcinoembryonic Antigen , Colorectal Neoplasms , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Follow-Up Studies , Humans , Neoplasm Recurrence, Local/surgery , Neoplasm Staging , Prognosis , Retrospective StudiesABSTRACT
The patient was a 66-year-old woman with a history of right breast cancer 20 years prior. Her chief complaint was hematochezia, and she was diagnosed as having rectal cancer. She underwent laparoscopic high anterior resection. We made a diagnosis of moderately differentiated adenocarcinoma, type 2, 25×20 mm, pMP, pN0, Stage I, KRAS being wild-type. Multiple liver metastases were detected 6 months after the surgery. Tumor contacted with grison. The tumor was not completely resected as evidenced by the small liver remnant volume. Conversion therapy was administered, and the patient received 6 courses of FOLFIRI plus cetuximab therapy. Alopecia and grade 1 eruption were observed as adverse effects of the chemotherapy. The tumor size was reduced, and we resected the tumor by performing right lobectomy and partial hepatectomy. At 1 year 3 months after surgery, no recurrence was observed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Liver Neoplasms/drug therapy , Rectal Neoplasms/drug therapy , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Cetuximab/administration & dosage , Colectomy , Combined Modality Therapy , Female , Fluorouracil/administration & dosage , Hepatectomy , Humans , Leucovorin/administration & dosage , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Rectal Neoplasms/pathology , Rectal Neoplasms/surgery , Treatment OutcomeABSTRACT
The first patient was a 62-year-old woman who was referred to our hospital with the complaint of a left breast tumor. She was diagnosed with invasive ductal carcinoma(T1N0M0, stage I). The tumor was ER-positive, PgR-negative, and HER2- negative. She was treated with toremifene, letrozole, and anastrozole as neoadjuvant hormone therapy for 4 months, but the tumor increased in size. The clinical response was judged as progressive disease, and a left partial mastectomy and axillary lymph node dissection were performed. Chemotherapy and radiotherapy were performed after surgery. The second patient was a 68-year-old woman who was referred to our hospital with the complaint of a right breast tumor. She was diagnosed as invasive ductal carcinoma(T1N0M0, stage I). The tumor was ER-positive, PgR-negative, and HER2-negative. She was treated with letrozole as neoadjuvant hormone therapy for 4 months, but the tumor increased in size. The clinical response was judged as progressive disease, and a right partial mastectomy and axillary lymph node dissection were performed. Chemotherapy and radiotherapy were performed after surgery. Although the evidence is still insufficient, with neoadjuvant hormone therapy for hormone-sensitive breast cancer, improved tumor shrinkage and breast conservation have been reported. We experienced two cases in which the tumor increased in size during neoadjuvant hormone therapy; however, even though these cases showed no apparent effect, chemotherapy may be effective in future cases.