Metastatic spread of disease is the cause of mortality in most cancers. Radiotherapy has traditionally had a prominent role in the treatment of localized disease but only a palliative role in the treatment of distant metastasis. The abscopal effect, regression or disappearance of tumor outside of the irradiated field, was first observed in the 1950s; however, it is quite rarely observed in routine clinical practice. With the use of immune modifiers, this effect has been increasingly reported. Our laboratory as well as several others have recently published studies that indicate that the abscopal effect in cancer treatment is mediated by the immune system. Unfortunately, in almost all cases, the anti-tumor action of the immune response that is triggered by local radiation treatment is inadequate on its own to fully eradicate distant tumors. Importantly, we have recently reported that anti PD-L1 and radiation decrease immunosuppression in irradiated tumors. Hypothesis: We propose that the immune response to local radiation can be augmented by modulation of factors that inhibit immune function. We hypothesize that a critical determinant of the abscopal effect is the level of immunosuppression and T cell dysfunction in the secondary tumor microenvironment. Notably, this hypothesis is novel and distinct from conventional theories of abscopal regression that cite APC function and T cell priming in the draining lymph node as the most important abscopal events.
Specific Aims : 1) Investigate the mechanisms that govern the capacity of radiotherapy and immunotherapeutic checkpoint blockade using blocking antibodies to PD-L1 to transform the tumor microenvironment into an immunological hub resulting in immune-mediated regression of distant disease and elimination of micrometastases that contribute to late relapse. Here we will focus on reducing immunosuppression in the irradiated tumor, which can influence T cell function in distant tumors; 2) Utilize the metastatic breast tumor line 4T1 to analyze the effect of local IR in combination with therapeutic delivery of the T cell and stromal modulator LIGHT and anti-PD-L1 antibodies for modulation of the tumor immune microenvironment to further enhance systemic immune activation. Here we will focus on improving T cell function as well as reducing immunosuppression. The results of these experiments will not only produce data pertaining to modulating abscopal effects, which will contribute significantly to the development of new, less toxic therapies for metatstatic cancer through the optimization of dose and timing of local IR that produces systemic effects in combination with immune therapies (anti-PD-L1 antibodies and LIGHT), but more importantly could lead to the transformation of radiotherapy from a palliative modality, in the presence of metastases, to a potentially curative modality.
The results of these experiments are highly relevant to public health because they could lead to the transformation of radiotherapy from a palliative modality, in the presence of metastases, to a potentially curative modality for metastatic cancer.
|Liang, Hua; Deng, Liufu; Hou, Yuzhu et al. (2017) Host STING-dependent MDSC mobilization drives extrinsic radiation resistance. Nat Commun 8:1736|
|Spiotto, Michael; Fu, Yang-Xin; Weichselbaum, Ralph R (2016) The intersection of radiotherapy and immunotherapy: mechanisms and clinical implications. Sci Immunol 1:|