Type and location of tumor‐infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients

Abstract

The type of tumor‐infiltrating macrophages may be decisive in tumor immunity, lymphangiogenesis and in the clinical outcome of cancer. Here, we elucidated the prognostic significance of lymphatic vessels, different types of macrophages and the balance between different macrophage types in colorectal cancer. We analyzed the impact of density, type and location of macrophages on the clinical behavior of 159 primary colorectal carcinomas using CD68 as a pan‐macrophage marker and CLEVER‐1/Stabilin‐1 as a marker for regulatory/suppressive macrophages. Podoplanin was used as a pan‐lymphatic vessel marker. A high number of CLEVER‐1/Stabilin‐1+ peritumoral macrophages positively correlated with survival (p = 0.04). However, in more advanced disease (Stage IV), the patients with a high number of peritumoral or intratumoral CLEVER‐1/Stabilin‐1+ macrophages had a shorter disease‐specific survival (p = 0.05, and p = 0.008, respectively). Moreover, a low number of suppressive intratumoral CLEVER‐1/Stabilin‐1+ macrophages among high numbers of CD68+ macrophages correlated with a low number of distant recurrences (p = 0.01) and to fewer disease relapses exclusively in the liver as well (p = 0.006). A high number of intratumoral lymphatics correlated with poor survival (p = 0.03). The results of this work suggest that the type of macrophages, number of lymphatic vessels and their location contribute to the clinical behavior of colorectal cancer in a disease stage‐specific manner.

Impact of Epidermal Growth Factor Receptor (EGFR) Cell Surface Expression Levels on Effector Mechanisms of EGFR Antibodies

“…3 and 4, it can be concluded that monocytes represent a potent effector cell population against tumor cells expressing low and high levels of EGFR, whereas PMNs encompass efficient antitumoral capacities only against tumor cells expressing high levels of EGFR. In tumor samples from patients, myeloid cells often constitute the predominant leukocyte tumor infiltrate, particularly if tumors contain necrotic areas (39,41,42). Tumor-promoting and tumor-inhibitory roles have been suggested for both monocytes/macrophages and PMNs based on in vivo studies in mice (43,44).…”

Characterization of a Mutated IgA2 Antibody of the m(1) Allotype against the Epidermal Growth Factor Receptor for the Recruitment of Monocytes and Macrophages

“…In tumor sections, myeloid cells, including tumor-associated macrophages, constitute the major component of the leukocyte tumor infiltrate (27,28); however, their potential role for tumor progression or surveillance is controversial. For example, experiments with cytokine-transfected tumor cells demonstrated inhibitory effects of the recruited myeloid cells on tumor growth (41, 42).…”

“…For the CD20 antibody rituximab, the innate mononuclear phagocyte network was demonstrated to be the predominant effector cell population in vivo (26). In tumor biopsies, macrophages constitute a major component of the leukocyte infiltrate, where monocyte-derived M0 macrophages are thought to polarize into the tumor-inhibiting M1 or the tumor-promoting M2 phenotypes (27,28). In vitro, both M1 and M2 macrophages phagocytosed human IgG1 antibody opsonized tumor cells (29), but the potential of these subpopulations as effector cells for IgA antibodies has not been investigated previously.…”

PLD4 promotes M1 macrophages to perform antitumor effects in colon cancer cells

“…The concept of cancer immune-surveillance has been supported by research showing that immune-deficiencies facilitate easy development of a neoplasm, further studies by animal models with inhibition of specific genes coding for the immune response resulted in a higher susceptibility to develop spontaneous or chemically-induced cancers (2,3). Previous studies showed that the infiltration of TAMs in colorectal cancer predicted a good prognosis (4)(5)(6)(7)(8). TAMs have been shown to be highly plastic cells that can display both tumor preventing (M1 macrophages) and tumor promoting functions (M2 macrophages) (9,10).…”