Ablative RT protects immune responses

In this issue of Blood, Lee et al provide a rationale for engaging the immune system by treating tumors with large, single-fraction radiation doses.

Advances in the technical aspects of radiation oncology have included improved tumor imaging, conformal treatment planning, and millimeter precision in radiation treatment delivery. However, optimal dose fractionation and integration of radiation therapy with other therapeutic modalities are undergoing redefinition. For selected cancer histologies and clinical presentations, conventional treatment approaches of delivering multiple daily fractions of radiation to relatively large volumes over intervals of 8 weeks or longer are evolving, due to the use of highly conformal hypofractionated stereotactic body radiation therapy (SBRT) or single fraction stereotactic radiosurgery (SRS). Such treatments are often less disruptive to patients' lives and appear to offer radiobiologic benefits, particularly for the treatment of cancers considered “radiation-resistant.” Hypofractionated radiation therapy has been advanced for the treatment of metastatic malignant melanomas, renal carcinomas, and sarcomas with generally favorable clinical responses, but wide acceptance of such an approach for treating primary tumors has been less enthusiastic, pending further experience with normal tissue late effects in patients. Recent SBRT applications have included aggressive therapy of lung and prostate cancers.^1,2 

In the work presented by Lee et al, ablative radiation therapy delivered in a single fraction was observed to reduce tumor burden at the primary site and in distant metastases in an animal tumor model by engaging the immune system through T-cell responses. In contrast, fractionated radiation therapy or the addition of adjuvant chemotherapy abrogated the radiation-induced immune responses.³  These observations in the murine model have clinical counterparts in the occasional tumor responses attributed to abscopal effects (outside the irradiated volume), and demonstrated to have an immunologic basis in an experimental model.⁴ 

Studies of radiation-induced immune modulation have identified critical roles for antigen presentation to dendritic cells leading to T-cell activation. Calreticulin has been recognized as a radiation-inducible protein, and roles in apoptosis, antigen presentation, and signaling dendritic cells have been attributed to this protein.^5,6  The report of differential effects of ablative radiation therapy as compared with fractionated radiation therapy or with the addition of adjuvant chemotherapy on T-cell responses offers critical clinical implications to be considered in the design of future combined modality therapeutic strategies. Can it be that the incremental progress anticipated from combining modalities is actually counterproductive in clinical settings conducive to a favorable immune response associated with radiation therapy? Does radiation fractionation or poorly sequenced adjuvant chemotherapy destroy the very cells responsible for a beneficial immune response?

The results described in the murine melanoma model suggest just that. Large single fractions of radiation therapy proved most compatible with a robust immune response. The addition of multiple fractions of radiation therapy over 2 weeks or adjuvant chemotherapy impaired the response, possibly by destroying the very cells responsible for antigen recognition, presentation, and T-cell stimulation. Although this report is unlikely to result in a substantial change in the current clinical approach to cancer treatment, there may be the opportunity to identify clinical settings for testing such a new paradigm.