TGFβ Inhibition Prior to Hypofractionated Radiation Enhances Efficacy in Preclinical Models

Abstract

The immune infiltrate in colorectal cancer has been correlated with outcome, such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage. For patients with lower immune infiltrates, overall survival is limited. Because the patients with colorectal cancer studied have received conventional cancer therapies, these data may indicate that the pretreatment tumor environment increases the efficacy of treatments such as chemotherapy, surgery, and radiotherapy. This study was designed to test the hypothesis that an improved immune environment in the tumor at the time of treatment will increase the efficacy of radiotherapy. We demonstrate that inhibition of TGFb using the orally available small-molecule inhibitor SM16 improved the immune environment of tumors in mice and significantly improved the efficacy of subsequent radiotherapy. This effect was not due to changes in radiosensitivity, epithelial-mesenchymal transition, or changes in vascular function in the tumor; rather, this effect was dependent on adaptive immunity and resulted in long-term protective immunity in cured mice. These data demonstrate that immunotherapy is an option to improve the immune status of patients with poor tumor infiltrates and that pretreatment improves the efficacy of radiotherapy.

Role of the immunosuppressive microenvironment in immunotherapy

“…TGFβ also inhibits the cytotoxicity of CD8 T cells 47 . Thus, inhibiting TGFβ has the potential to disrupt the immunosuppressive TME on multiple fronts, and preclinical studies have shown improved tumor responses to radiation when combined with TGFβ inhibition 48, 49…”

Hypofractionated Irradiation Has Immune Stimulatory Potential and Induces a Timely Restricted Infiltration of Immune Cells in Colon Cancer Tumors

“…Extensive efforts to improve the clinical management of patients with colorectal cancer have been made, but approved treatments only offer limited survival benefit. Therefore, alternative therapeutic strategies such as radioimmunotherapy need to be explored with preclinical animal models (16, 17). It has already become evident that the immune infiltrate including type, density, and location of immune cells within human colorectal tumors predict clinical outcome such that individuals with higher infiltrations of T cells have increased survival independent of the disease stage (18).…”

Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination

“…However, TGF-beta blockade in this model was unable to mediate a significant anti-tumor effect, either alone, combined with RT or with LM-based vaccination. Those data are perhaps somewhat contradictory to recent studies demonstrating that blocking TGF-β prior to hypofractionated radiation enhances preclinical responses (35), and additional work will be required to determine whether these differences reflect the use of different TGF-β blocking agents, the location of the tumor, or the cancer model under study. While our studies focused on microglia and antigen-presenting cells in the tumor draining lymph nodes and spleen, it is clear that tolerance to tumor antigens is mediated by a number of additional myeloid cell types, particularly myeloid derived suppressor cells (MDSC) (31).…”