Effects of tumor growth on host defenses

Abstract

Monocytes and macrophages play an important role in host defense against neoplasia. Studies from our and other laboratories have demonstrated that patients with a variety of cancers have a defect in monocyte chemotactic responses. Tumor-bearing mice are also inhibited in their ability to accumulate macrophages to inflammatory foci. We have shown that extracts prepared from murine tumors, as well as the plasma and urine of tumor-bearing mice, contain anti-inflammatory proteins which are antigenically and physicochemically related to the immunosuppressive retroviral envelope protein p15E. Similarly, proteins capable of inhibiting monocyte chemotactic responses are present in human cancerous effusions and can be specifically absorbed by monoclonal antibodies to p15E. Furthermore, we have demonstrated that human malignant and mitogen-transformed cells contain p15E-related antigens. These findings led us to propose a two stage model of tumorigenesis: the first stage involves neoplastic transformation of a cell while the second stage involves activation of a gene coding for a p15E-like protein which allows the transformed cell to escape immune surveillance and go on to become a tumor. Support for this model has come from recent studies which have identified within the human genome an endogenous retrovirus sequence whose envelope gene is partially homologous to a highly conserved region of p15E. Using a synthetic peptide, termed CKS-17, we have shown that this region may be responsible for many of the biological activities of p15E and is capable of suppressing lymphocyte and natural killer cell immune functions as well as those of monocytes and macrophages. Thus tumors may be capable of evading host defense mechanisms by activation of a normal gene related to the immunosuppressive retroviral protein p15E.

The immunodominant major histocompatibility complex class I-restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product.

“…For example, transcriptional regulation of expression of the human endogenous retroviral gene product, HERV-K, has been demonstrated in the hormone-sensitive human breast tumor line, T47D (52,53 (54). Furthermore, the expression of a chemotactic inhibitory protein, which has an immunological cross-reactivity to the MuLV envelope protein plSE, has been detected in the effusions of patients with squamous cell carcinoma, melanoma, and carcinoma of the bladder (55). Taken together, these findings support the further analysis of endogenous retroviral gene products as immunologically relevant human tumor antigens.…”

Suppressive effect on polyclonal B-cell activation of a synthetic peptide homologous to a transmembrane component of oncogenic retroviruses.

“…Indeed, it has been established that the transmembrane envelope protein pl5E present in feline, murine, or bovine leukemia viruses, suppresses a number of lymphoid cell functions (13)(14)(15)(16). Recently, Cianciolo et al (17) synthesized a 17-amino acid peptide (CKS-17), which exhibits a striking homology to the transmembrane peptides present in many animal and human retroviruses (e.g., HTLV-I, HTLV-II, feline, murine, bovine, avian, and simian retroviruses) (18)(19)(20). This peptide also suppresses in vitro the respiratory burst of human monocytes (21), interleukin 2-induced proliferation of an interleukin 2-dependent murine T-cell line, and proliferative reactions of human or murine lymphocytes in mixed lymphocyte cultures (17).…”

in vitro proliferative responses of spleen lymphocytes from rats bearing progressive or regressive tumors induced by cell variants of a syngeneic colon carcinoma

“…The suppressive effect found in our work is at least partly non-specific, as demonstrated by the inhibition of PHA-induced proliferation. Suppression can be mediated by several non-specific factors (Balch et al, 1984;Ciancolo, 1986). PROb cells could directly elaborate these non-specific immunosuppressive factors or trigger their secretion by macrophages, as reported for other systems (Ting and Hargrove, 1982;Pillay et al, 1986).…”