The adaptive immune system is comprised of a number of different cell types. Among them are B cells (derived from bone marrow) and T cells (derived from the thymus).
B cells are responsible for the familiar “memory” function of the immune system. They recognize pathogens and cancer and alert the immune system to clear them. A subset of T cells, helper T cells, assist in the immune response.
However, if uncontrolled, the activity of B and T helper cells can be excessive or out of control, and requires regulation. That is the role of regulatory T (Treg) cells.
Tregs in cancer
One important role of the immune system is monitoring for cells that have become malignant, and could potentially lead to cancer, and eliminating those cells. Tregs play a role in the immunosurveillance process, at times hindering efficient eradication of tumors.
A number of studies have revealed the role played by Tregs in solid malignancies. For example, in ovarian and non-small-cell lung cancer (NSCLC), increased levels of Tregs were found in circulation and within tumor-infiltrating lymphocytes. The Tregs inhibited proliferation of other types of T cells and production of interferon γ (IFN-γ), a type of cytokine that triggers response of the adaptive immune system.
Similar results have been seen in pancreatic and breast cancer, and in colon cancer. CD4+CD25+ Tregs have been shown to suppress natural killer (NK) cell-mediated cytotoxicity in epithelial tumors such as lung, breast, and colorectal.
Not all of the effects of Tregs in solid tumors have been observed to be negative with respect to disease progression, however. Some studies show that the presence of Tregs was correlated with a positive prognosis--for example, head-and-neck cancer. This suggests a more complex role for Tregs in cancer.
Since carcinogenesis is an inflammation-mediated process, Tregs may counteract inflammatory processes, allowing a more effective anticarcinogenic effect.
Tregs can be induced or expanded through the use of cancer vaccines. Since Tregs generally suppress immune responses, this can become an obstacle to effective cancer immunotherapy. Treg depletion is increasingly being considered as an adjuvant therapy for a cancer vaccine approach.
Some approaches for targeting Tregs in cancer therapy include:
Depletion of Tregs: Alkylating agents are the gold standard for the treatment of many cancers. Low-doses of some alkylating agents have been found to have an immunostimulatory effect due to depletion of Tregs. Another approach for depletion of Tregs is by targeting CD25 with monoclonal antibodies.
Targeting the function of Tregs: Blocking the function of CTLA-4, a molecule expressed by Tregs, can block the function of Tregs, potentially leading to greater efficacy of immunotherapy in cancer. Investigational anti-CTLA-4 antibodies have been tested in early clinical trials with mixed results.
Disruption of intratumoral homing of Tregs: Tregs migrate into the tumor microenvironment in response to chemokine receptor interactions. The interaction between the chemokine CCL22 secreted by a tumor, and CCR4, which is expressed on Tregs, is a crucial interaction. Blocking of CCL22 has been shown to reduce migration of Tregs into ovarian tumors.
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