Faculty Bibliography

Abstract Changes in activity or levels of transforming growth factor-beta (TGF-beta) are associated with a variety of diseases; however, measurement of TGF-beta in biological fluids is highly variable. TGF-beta is biologically inert when associated with its latency-associated peptide (LAP). Most available immunoassays require exogenous activation by acid/heat to release TGF-beta from the latent complex. We developed a novel electrochemiluminescence-based multiplexed assay on the MesoScale Discovery(R) platform that eliminates artificial activation, simultaneously measures both active TGF-beta1 and LAP1 and includes an internal control for platelet-derived TGF-beta contamination in blood specimens. We optimized this assay to evaluate plasma levels as a function of activation type and clinical specimen preparation. We determined that breast cancer patients' plasma have higher levels of circulating latent TGF-beta (LTGF-beta) as measured by LAP1 than healthy volunteers (p < 0.0001). This assay provides a robust tool for correlative studies of LTGF-beta levels with disease, treatment outcomes and toxicity with a broad clinical applicability.

The discrepancy between the in vitro and in vivo response to radiation is readily explained by the fact that tumors do not exist independently of the host organism; cancer cells grow in the context of a complex microenvironment composed of stromal cells, vasculature, and elements of the immune system. As the antitumor effect of radiotherapy depends in part on the immune system, and myeloid-derived cells in the tumor microenvironment modulate the immune response to tumors, it follows that understanding the effect of radiation on myeloid cells in the tumor is likely to be essential for comprehending the antitumor effects of radiotherapy. In this review, we describe the phenotype and function of these myeloid-derived cells, and stress the complexity of studying this important cell compartment owing to its intrinsic plasticity. With regard to the response to radiation of myeloid cells in the tumor, evidence has emerged demonstrating that it is both model and dose dependent. Deciphering the effects of myeloid-derived cells in tumors, particularly in irradiated tumors, is key for attempting to pharmacologically modulate their actions in the clinic as part of cancer therapy.

Preclinical evidence of successful combinations of ionizing radiation with immunotherapy has inspired testing the translation of these results to the clinic. Interestingly, the preclinical work has consistently predicted the responses encountered in clinical trials. The first example came from a proof-of-principle trial started in 2001 that tested the concept that growth factors acting on antigen-presenting cells improve presentation of tumor antigens released by radiation and induce an abscopal effect. Granulocyte-macrophage colony-stimulating factor was administered during radiotherapy to a metastatic site in patients with metastatic solid tumors to translate evidence obtained in a murine model of syngeneic mammary carcinoma treated with cytokine FLT-3L and radiation. Subsequent clinical availability of vaccines and immune checkpoint inhibitors has triggered a wave of enthusiasm for testing them in combination with radiotherapy. Examples of ongoing clinical trials are described in this report. Importantly, most of these trials include careful immune monitoring of the patients enrolled and will generate important data about the proimmunogenic effects of radiation in combination with a variety of immune modulators, in different disease settings. Results of these studies are building a platform of evidence for radiotherapy as an adjuvant to immunotherapy and encourage the growth of this novel field of radiation oncology.