Sensors of ionizing radiation effects on the immunological microenvironment of cancer

Purpose: When cancer develops in an immunocompetent host it represents the result of a successful deception of the immune system as to the nature of the danger and the type of response needed to reject the neoplastic tissue. We will briefly review some of the recently emerged evidence that irradiation of the tumor and its microenvironment can induce essential molecular signals required for an effective response of the immune system to the tumor. Conclusions: The subversion of a highly organized tissue architecture is a hallmark of cancer, and results in uneven distribution of oxygen and nutrients, interstitial pressure gradients and areas of patchy necrosis and inflammation. In this microenvironment, cancer cells that carry mutations favoring survival rather than cell death in response to stress find a selection advantage. Importantly, the signals derived from the disruption of orderly physiology within tissues are also what the immune system has evolved to respond to. The type of response is tuned to be adequate to the cause of the disruption. An infectious organism will carry or elicit from the involved tissue a number of `danger signals' leading to development of cell mediated and humoral responses to both eliminating the invader and preventing future infections. In contrast, a simple wound will call for a repair response. The sensors of the type of damage are complex molecular interactions between the damaged organ and cells of the innate and adaptive immune system. Progress in the identification of these interactions elucidates which pathways are specifically altered in cancer. It also provides a novel understanding of the radiation-induced effects on tumor immunogenicity. We propose that specific radiation-induced effects could be successfully exploited to improve the effectiveness of immunotherapy.