Effects of conventional therapeutic interventions on the number and function of regulatory T cells

Abstract

Several lines of investigation have revealed the apparent interplay between the immune system of the host and many conventional, “standard-of-care” anticancer therapies, including chemotherapy and small molecule targeted therapeutics. In particular, preclinical and clinical studies have demonstrated the important role of regulatory T cells (Tregs) in inhibiting immune responses elicited by immunotherapeutic regimens such as those based on anticancer vaccines or checkpoint inhibitors. However, how the number and immunosuppressive function of Tregs change in cancer patients undergoing treatment with non-immune anticancer therapies remains to be precisely elucidated. To determine whether immunostimulatory therapies can be employed successfully in combination with conventional anticancer regimens, we have investigated both the number and function of Tregs obtained from the peripheral blood of carcinoma patients before the initiation and during the course of chemotherapeutic and targeted agent regimens. Our studies show that the treatment of breast cancer patients with tamoxifen plus leuprolide, a gonadotropin releasing hormone agonist, has minimal effects on Tregs, while sunitinib appears to exert differential effects on Tregs among patients with metastatic renal carcinoma. However, the administration of docetaxel to patients with metastatic prostate or breast cancer, as well as that of cisplatin plus vinorelbine to non-small cell lung cancer patients, appears to significantly increase the ratio between effector T cells and Tregs and to reduce the immunosuppressive activity of the latter in the majority of patients. These studies provide the rationale for the selective use of active immunotherapy regimens in combination with specific standard-of-care therapies to achieve the most beneficial clinical outcome among carcinoma patients.

The importance of correctly timing cancer immunotherapy

“…A selective decrease in MDSCs was also observed after treatment with 5-fluorouracil (5-FU) [102]. The combination of cisplatin plus vinorelbine appears to significantly increase the ratio between effector T-cells and Tregs and to reduce the immunosuppressive activity of the latter in the blood of the majority of non-small cell lung cancer patients [103]. Therefore, modulation of immune suppressive cells by chemotherapeutic agents prior to anticancer vaccine could explain the additive or synergistic antitumor effect of combined chemotherapy and immunotherapy.…”

Antitumor Effects of Cisplatin Combined with Tecemotide Immunotherapy in a Human MUC1 Transgenic Lung Cancer Mouse Model

“…As is hypothesized for cyclophosphamide, the effects of chemotherapy on the number and function of regulatory T cells (Treg) may be involved in cisplatin's antitumor effects. A recent study suggests that some chemotherapeutic regimens, such as docetaxel in metastatic breast cancer and castration-resistant prostate cancer, and the combination of cisplatin and vinorelbine in NSCLC, may suppress Treg activity and increase the ratio of T-effector cells to Tregs, while other therapeutic regimens have mixed effects on Tregs, such as tamoxifen combined with leuprolide in breast cancer, and sunitinib in metastatic renal cell carcinoma (24). Clinically, and in the present study, low-dose cyclophosphamide is administered 3 days before starting each cycle of tecemotide.…”

Enabling T Cell Recruitment to Tumours as a Strategy for Improving Adoptive T Cell Therapy

“…Treg-recruitment to the tumour. [118][119][120] In vitro, some truncated chemokines can act as antagonists to their cognate receptors such as CXCL8, CCL5 and CCL2. [121][122][123] Several antibodies targeting chemokine ligands are being tested for tumour immunotherapy.…”