By the Blouin News Science & Health staff

Undercover tumors caught in action

by in Research.

A sign pointing to the Rebecca and John Moores UCSD Cancer Center DNA Sequencing facility at the UCSD in San Diego, CA

(REUTER/Mike Blake)

Tumors have several mechanisms to help them pass undetected from the attention of the immune system. One of them is the recruit of immunosuppressive T cells to create an environment around them in which immune system is suppressed. A new study published in the journal Science (8 March) by the group of Peter Savage, from Department of Pathology, University of Chicago, U.S.A., surprisingly showed that this recruitment is the result of antigens present in the normal tissue from which the tumor arises, and not in the tumor itself.

Regulatory T (Treg) cells are lymphocytes, which have been rendered immunosuppressive in the thymous, the gland in which the maturation of all T cells takes place, so that they do not recognize the self-antigens and initiate an autoimmune reaction. But Treg cells are also found to infiltrate the microenvironment of tumors (tumor-infiltrating Treg) and they have been associated with tumor survival. But we do not know why and how this is done.

A systematic review of about 60 studies from 16 cancer types published in Clinical Cancer Research by researchers of the Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, University of Victoria, Canada, concluded that a certain type of Treg cells (expressing the protein FoxP3; FoxP3+ Treg cells) was mainly associated with the infiltration. But their function is not very clear as about 20% of the tumors showed good prognosis while the majority showed poor prognosis. Similarly, contradictory findings were found by West et al., who noticed that FoxP3+ Treg cells were associated with good prognosis in some types of breast cancer.

Therefore, the site of tumor seems to play an important role but the factors that drive tumor immunity are yet unknown. So what attracts infiltrating immunosuppresive Treg cells to the tumor?

Working towards this direction, Malchow and colleagues from the Savage group used a genetically modified mouse model which develops prostatic adenocarcinomas and studied the distribution of infiltrating Treg cells. A significant increase in the number of such Treg cells was confirmed in the prostate of the mutant mice as well as in the lymph nodes associated with the prostate, compared to cancer-free mice. But when they looked at the T cell receptors (TCR), the receptors that recognize the antigens, they unexpectedly found that these Treg cells were recognizing antigens of normal prostate tissue rather than any antigen of the tumor. This way, the Treg cells were surrounding the area, including both the tumor and normal tissue with the lymph nodes, to suppress activity of the immune system locally.

Therefore, it is conceivable that tumors do not alter the normal development of Treg cells but change their distribution in the body and recruit these Treg cells to establish local immunosuppression and protection from the host immune system.

This is an important finding because it would direct future research towards the Treg cells recognizing normal tissues, too, not only tumors.  It would potentially contribute to the development of effective therapies against tumor immunity and improve cancer immunosurveillance. However, several questions arise by these new findings, as expressed by Nikhil S. Joshi and Tyler Jacks, who did not participate in the study, in their Perspectives article in Science. Do these infiltrating Treg cells actively suppress the immune system against tumors and why they are there in the first place? Does this apply to other tumor types? It is also thought that tumors initiate the synthesis of de novo (new) tumor-specific Treg cells in order to evade immune system attacks. What is their relationship with normal tissue Treg cells? In sites of metastasis, are Treg cells reactive to tissue-specific antigens of the primary site or of the secondary?

As always, new results provoke more questions which, when answered, will eventually provide vital information for the development of therapies that improve the immune response against tumors.