Dataset Information

Expression and Prognostic Significance of CD47-SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer.

ABSTRACT: Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observations, drugs targeting the macrophage checkpoint have been developed with the expectation of anti-cancer effects against T-cell immune checkpoint inhibitor-refractory tumors. In the present study, 269 primary CRCs were evaluated immunohistochemically for CD47, SIRPA, CD68, and CD163 expression to assess their predictive utility and the applicability of CD47-SIRPA axis-modulating drugs. Thirty-five percent of the lesions (95/269) displayed CD47 expression on the cytomembrane of CRC cells. CRCs contained various numbers of tumor-associated immune cells (TAIs) with SIRPA, CD68, or CD163 expression. The log-rank test revealed that patients with CD47-positive CRCs had significantly worse survival than CD47-negative patients. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio (R) = 0.23), age < 70 years (HR = 0.48), and high SIRPA-positive TAI counts (HR = 0.55) as potential favorable factors. High tumor CD47 expression (HR = 1.75), lymph node metastasis (HR = 2.26), and peritoneal metastasis (HR = 5.80) were cited as potential independent risk factors. Based on our observations, CD47-SIRPA pathway-modulating therapies may be effective in patients with CRC.

SUBMITTER: Sugimura-Nagata A

PROVIDER: S-EPMC7975978 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Expression and Prognostic Significance of CD47-SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer.

Sugimura-Nagata Akane A Koshino Akira A Inoue Satoshi S Matsuo-Nagano Aya A Komura Masayuki M Riku Miho M Ito Hideaki H Inoko Akihito A Murakami Hideki H Ebi Masahide M Ogasawara Naotaka N Tsuzuki Toyonori T Takahashi Satoru S Kasugai Kunio K Kasai Kenji K Inaguma Shingo S

International journal of molecular sciences 20210307 5

Despite the confirmed anti-cancer effects of T-cell immune checkpoint inhibitors, in colorectal cancer (CRC) they are only effective in a small subset of patients with microsatellite-unstable tumors. Thus, therapeutics targeting other types of CRCs or tumors refractory to T-cell checkpoint inhibitors are desired. The binding of aberrantly expressed CD47 on tumor cells to signal regulatory protein-alpha (SIRPA) on macrophages allows tumor cells to evade immune destruction. Based on these observat ...[more]

PMID: 33799989

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Project description:Integrin-associated protein (CD47) is ubiquitously expressed on the surface of cells and functions as an identifier of self. In blood cancer, tumor cells expressing CD47 evade phagocytosis by macrophages, leading to a poor patient prognosis. However, the status of CD47 expression in solid tumors, particularly in gastric cancer, is not well understood. The purpose of the present study was to examine the level of CD47 in the primary tumor, peripheral blood (PB) and bone marrow (BM) of patients with gastric cancer, and to determine its effect. Reverse transcription-quantitative polymerase chain reaction analysis was performed to determine the level of CD47 mRNA expression in primary tumor, PB and BM samples collected from 168 patients with gastric cancer. Cell sorting was performed to investigate CD47 protein expression in PB and BM fractions, and to identify the source of CD47 expression. In primary tumors, the expression of CD47 was not associated with any clinicopathological factors or prognosis. By contrast, in PB, the low CD47 expression group demonstrated a significantly increased tumor size, and frequency of lymphatic invasion and lymph node metastasis, compared with the high CD47 expression group. In addition, the clinical tumor stage of the low CD47 expression group was significantly increased compared with that of the high CD47 expression group. Conversely, in PB, the high CD47 expression group had a significantly higher frequency of lymphatic invasion and lymph node metastasis compared with the low CD47 expression group. The lymphocyte fraction exhibited the highest CD47 expression compared with the other fractions in PB and BM samples. Low expression of CD47 was associated with the advancement of gastric cancer, in contrast to other cancers, and it may be associated with a decrease in lymphocytes during later stages. These results indicate that CD47 expression in the PB and BM may serve as a marker to analyze the immunological function of patients with gastric cancer; however, the significance of CD47 in gastric cancer requires further study.

Project description:BACKGROUND: Special AT-rich sequence-binding protein 1 (SATB1) is a global gene regulator that has been reported to confer malignant behavior and associate with poor prognosis in several cancer forms. SATB1 expression has been demonstrated to correlate with unfavourable tumour characteristics in rectal cancer, but its association with clinical outcome in colorectal cancer (CRC) remains unclear. In this study, we examined the prognostic impact of SATB1 expression in CRC, and its association with important molecular characteristics; i.e. beta-catenin overexpression, microsatellite instability (MSI) screening status, and SATB2 expression. METHODS: Immunohistochemical expression of SATB1 and beta-catenin was assessed in tissue microarrays with tumours from 529 incident CRC cases in the prospective population-based Malmö Diet and Cancer Study, previously analysed for SATB2 expression and MSI screening status. Spearmans Rho and Chi-Square tests were used to explore correlations between SATB1 expression, clinicopathological and investigative parameters. Kaplan Meier analysis and Cox proportional hazards modelling were used to explore the impact of SATB1 expression on cancer specific survival (CSS) and overall survival (OS). RESULTS: SATB1 was expressed in 222 (42%) CRC cases and negative, or sparsely expressed, in adjacent colorectal mucosa (n?=?16). SATB1 expression was significantly associated with microsatellite stable tumours (p?<?0.001), beta-catenin overexpression (p?<?0.001) and SATB2 expression (p?<?0.001). While not prognostic in the full cohort, SATB1 expression was significantly associated with poor prognosis in SATB2 negative tumours (HR?=?2.63; 95% CI 1.46-4.71; p(interaction)?=?0.011 for CSS and HR?=?2.31; 95% CI 1.32-4.04; p(interaction)?=?0.015 for OS), remaining significant in multivariable analysis. CONCLUSIONS: The results of this study demonstrate that SATB1 expression in CRC is significantly associated with beta-catenin overexpression, microsatellite stability and SATB2 expression. Furthermore, SATB1 expression is a factor of poor prognosis in SATB2 negative tumours. Altogether, these data indicate an important role for SATB1 in colorectal carcinogenesis and suggest prognostically antagonistic effects of SATB1 and SATB2. The mechanistic basis for these observations warrants further study. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1922643082772076.

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Dataset Information

Expression and Prognostic Significance of CD47-SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer.

Publications

Expression and Prognostic Significance of CD47-SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer.

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