Abundant intratumoral fibrosis prevents lymphocyte infiltration into peritoneal metastases of colorectal cancer

Abstract

Background Tumor-infiltrating lymphocytes (TILs) have been reported to reflect the anti-tumor immune status. However, recent investigations have demonstrated that intratumoral fibrosis is important as a factor affecting the infiltration of TILs. This study investigated the organ specificities of TIL infiltration and intratumoral fibrosis in primary colorectal cancer and distant metastases, as well as the relationship between the distribution of TILs and intratumoral fibrosis. Methods Patients who underwent resection of primary tumors or distant metastases for colorectal cancer with distant metastases were enrolled. We evaluated the TIL infiltration by immunohistochemical staining with CD3&CD8 and intratumoral fibrosis by immunohistochemical staining with α-SMA positive cancer-associated fibroblasts and Masson’s trichrome staining against collagen fibers. The "ImageJ" was used to evaluate fibrosis, and the density of TILs in the dense and sparse areas of fibrosis was calculated. The Immunoscore (IS) was obtained based on the density of CD3+/CD8+TILs in the tumor center and invasive margin of the primary tumor. Results The degree of CD3+/CD8+TIL infiltration in peritoneal metastases was significantly lower than that in liver and lung metastases. The area ratio of α-SMA positive cancer-associated fibroblasts and collagen fibers in peritoneal metastases was significantly higher than that of liver and lung metastases. Furthermore, the density of TILs in the high-fibrosis area was significantly lower than that in the low-fibrosis area. In the high-IS group of primary tumors, the degree of TIL infiltration in distant metastases was significantly higher than that in the low-IS group. Conclusion The infiltration of T lymphocytes into tumors is prevented in peritoneal metastases of colorectal cancer due to the high intratumoral fibrosis, which may lead to treatment resistance and a poor prognosis.

Type XXII Collagen Complements Fibrillar Collagens in the Serological Assessment of Tumor Fibrosis and the Outcome in Pancreatic Cancer

“…The lack of a general discrepancy in (PRO-C1 and PRO-C3) biomarker levels in the serum from healthy subjects and cancer patients in Cohort 1 might be caused by the already high systemic levels, since COL1 and COL3 are the most abundant collagens [ 57 ]. PRO-C3 was significantly elevated in the serum from patients with colorectal and pancreatic cancer, malignancies, known to have a deposition of fibrillar collagens [ 58 , 59 , 60 ], and a high PRO-C3 has previously been associated with mortality in cancer patients with a metastatic disease [ 19 , 61 , 62 ].…”

Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment

“…Previously, we could show that infiltration of CD4 + T-cells in human PC specimens is significantly reduced compared with primary tumor samples ( 10 ). The group Ohira group also showed that infiltration of CD8 + T cells in peritoneal metastasis is also reduced compared with liver and lung metastasis ( 57 ). In our mouse model, the degree of CD8 + T-cell infiltration was significantly reduced compared with primary tumor and liver metastasis samples, showing that our new mouse model truly recapitulates the clinical setting of human peritoneal carcinomatosis.…”

Molecular Mechanisms of Tumor Immunomodulation in the Microenvironment of Colorectal Cancer

“…For example, Kuczek et al demonstrated that dense collagen matrices reduce proliferation and cytotoxic activities of T cells in vitro [ 164 ]. Similarly, it was observed in vivo that the fibrotic environment of CRC peritoneal metastases blocks T cells infiltration [ 165 , 166 ]. Conversely, while the stiff ECM may act as a physical barrier to T cells, dense collagen-rich ECM promotes macrophage infiltration and an immunosuppressive phenotype [ 167 ].…”