Selection of radiation protocols to enhance anti-tumor immunity
Nicholas Battaglia’s work focuses on studying how multiple factors affect the anti-tumor immune response following radiotherapy (RT). Specifically, his work examines how hypofractionated and ablative RT schedules lead to different patient outcomes despite delivering equivalent biologically effective doses in terms of resulting DNA damage. This work has shown that both radiotherapy schedules require an anti-tumor immune response for efficacy, though fractionated RT skews the tumor microenvironment to be more immunologically quiescent.
In addition, Nicholas’ work studies how combination therapy affects the RT mediated anti-tumor immune response. Radiotherapy is often accompanied by use of steroids, such as dexamethasone, to relieve pain and edema. Despite the necessity of these drugs, they are often immunosuppressive and thus may limit the antitumor immune response elicited by radiotherapy. Studying how steroids alter the immune response to RT is increasingly important as immunotherapy gains prominence in cancer treatment. Regarding immunotherapy, Nicholas’ work has also shown that Qa-1b, a ligand that stimulates the regulatory receptor NKG2A on T and NK cells, is upregulated following RT. Blockade of Qa-1b together with RT offers an exciting new immunotherapy to be used in conjunction with RT.
Crosstalk between the nervous and immune systems within the tumor microenvironment
A new project in the laboratory is a collaborative project with Dr. Scott Gerber in the Center for Tumor Immunology Research and Dr. Elizabeth Repasky at the Roswell Park Cancer Institute. Preliminary studies have revealed a role for the growth of nerves in the tumor microenvironment in tumor-promotion and survival. Sympathetic nerves and the neurotransmitter norepinephrine, acting through beta-adrenergic receptors appear to shape both the sensitivity of tumor cells to radiation therapy and the immune contexture of tumors. We are testing the hypothesis that drugs which block the ability of norepinephrine to signal through the beta-adrenergic receptors could improve the clinical efficacy of radiation.
Radiation treatment alters the tumor microenvironment
The tumor microenvironment with its chaotic vasculature and its myriad of immune and stromal cells is largely immunosuppressive. The low oxygen levels (hypoxia) present due to the largely nonfunctional vessels greatly limits the effectiveness of radiation therapy (RT) because of the absence of oxygen free radicals needed to cause DNA damage and the nondividing nature of hypoxic tumor cells. Interestingly, RT appears to diminish the extent of hypoxia, perhaps by killing large numbers of oxygen consuming tumor cells. In addition, the stimulation of immunity results in increased numbers of cells producing interferon-gamma, which causes the up-regulation of MCH class I and other molecules needed for immune stimulation. However, RT can also have detrimental effects as immune cells are highly radiosensitive. In our studies we are exploring this delicate balance and combining therapies for better clinical efficacy.