Antitumor-associated antigens IgGs: dual positive and negative potential effects for cancer therapy.

Abstract

Antitumor antigen antibodies are promising tools for cancer therapy, under the judgment of achieving targeted cell destruction. However, antibodies can not only kill tumor cells, but also trigger inflammation in the core of the tumor. Inflammation and cancer have been firmly associated for the last 10 years. Even if this connection was known by intuition since the late 1800s, solid demonstrations of molecular mechanisms behind it have been reported only recently. Nevertheless, basic antiinflammatory factors such as aspirin, and other COX inhibitors, all act somehow as good preventive drugs, but not as therapeutic agents. We have studied the inflammatory pathways associated with tumor cell invasion and metastasis, by analyzing triggers and brittle links in the chain of inflammatory events that promote cancer recurrence and metastasis. In our experiments we observed that signals through TNFalpha and lymphotoxin-alpha (LTalpha) constitute weak links in the tumor-promoting inflammatory scenario. Using gene-targeted mutations, we demonstrated that p55TNF-R blockade could reduce metastasis outcome in mice up to 50%. Likewise, LTalpha blockade reduces mortality in tumor-challenged and untreated mice by 10%, and 54% in mice treated with simple surgical tumor ablation. Conversely, p75TNF-R blockade increases metastasis outcome up to 200%. All taken together these results demonstrate that protumor inflammatory signals transmitted through TNF receptors are not complementary, but opposed: p55TNF-R mediates promalignancy inflammation and p75TNF-R quenches that pathway. Among the triggers of promalignancy inflammatory mechanisms, we demonstrated, that IgGs developed against soluble and shed tumor associated antigens (sTTA) are a major trigger of protumor inflammation. We also demonstrated that by knocking out the B cell receptor (BCR), mice do not develop anti-sTTA IgGs, 90% of mice reject the tumor challenge entirely, and from the 10% that develop tumor, only 20% recur after tumor ablation. Cloning and investigating the IgG-VH sequences, transcribed in lymphocytes and plasma cells, from bone marrow, spleen, and tumor stroma, we also observed that tumor infiltrating plasma cells produce a distinctive family of IgGs. The induction of random expression of these VH peptide sequences in mice, by in vivo transfection into muscle cells, with VH expressing vectors, reduced tumor progression in a significant manner. All these studies indicate that: (1) The use of TNF blockers (such as infliximab and adalimumab) and p55TNF-R blockers (such as lenercept) may have therapeutic benefit in oncology. (2) p75TNF-R blockers (such as etanercept) could be detrimental in oncology. (3) Active or passive immunization against sTAA, such as sTn and others, could be absolutely detrimental in cancer immune therapy. (4) Active or passive humoral immunization against membrane integrated tumor cell antigens should be carefully tested. (5) Investigation of IgG expressed in tumor infiltrating lymphoid cells, could convey important knowledge about the immune responsibility in tumor progression.