Combining Thoracic Irradiation and An Anti-PD-1 Antibody Decreases Survival Through Increased T Cell Infiltration into Cardiac and Lung Tissue

Lung cancer is the leading cause of cancer-related mortality in the United States. Radiation, a common component of treatment, can cause acute damage to critical organs including the lungs and the heart, but the serious toxicities from radiotherapy alone is relatively rare. A recent addition to the treatment regimen is immunotherapy, including the blockage of programmed death cell protein (PD-1) using anti-PD-1 antibody, which blocks the inhibition of activated T cells. Combining anti-PD-1 treatment and thoracic radiation has potential for improving the outcomes of locally advanced lung cancer over traditional chemoradiation regimens, but the effect of combining these therapies on normal lung tissue has not yet been investigated in preclinical models. In this work we studied the effect of combining anti-PD-1 blocking antibody with irradiation on tumor growth in the Lewis lung carcinoma (LLC) model in C57Bl/6 mice and the effect of combining this antibody with thoracic radiation on the tissues of the heart and lung. We found that this combination therapy was effective in delaying tumor growth, but decreased survival in animals undergoing thoracic radiation. The mechanism of this decrease is associated with T cell infiltration into lung and heart tissue, particularly CD4+ T cells. As combination therapy is becoming increasingly popular for the treatment of a variety of cancers, understanding the potential side effects and toxicities of these treatments is paramount. Thus, our findings have potentially serious implications for the combination of radiation and immunotherapy in lung cancer treatment