Abstract SY31-02: The interplay of radiotherapy with the tumour microenvironment: Novel opportunities to overcome adaptive resistance
Authors: Illidge Tim M. 
Published: July 2016

Abstract
Radiation Therapy (RT) is a highly effective anti-cancer treatment delivered to approximately 50 - 60% of all cancer patients, In addition to the direct tumor cell kill, emerging evidence suggests that RT has important effects on the tumor microenvironment and can generate anti-tumor immunity. RT induced tumor cell death is known to lead to increased ecto-calreticulin and tumor antigen expression as well as the release of several damage-associated molecular patterns (DAMPs). These “danger signals” include High Mobility Group Box 1 (HMGB1) and ATP which can lead to recruitment and activation of antigen presenting cells (APCs) and priming of tumor antigen-specific T cell responses. Despite these immunomodulatory properties of RT, systemic anti-tumor immune responses leading to clinically meaningful anti-tumor responses outside of the irradiated tumor field the so called the “abscopal effect” are rare in routine clinical practice. This lack of clinically meaningful abscopal effect is thought to be secondary to the immunosuppressive nature of the tumor microenvironment (TME), including Myeloid Derived Suppressor Cells (MDSC), Foxp3 T regulatory cells (Tregs) or blocking inhibitory molecules such as Programmed cell death protein 1 (PD-1), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); (LAG-3) Lymphocyte-activation gene 3, T-cell immunoglobulin and mucin-domain containing-3 (Tim-3),receptors or inhibitory cytokines including Transforming Growth Factor (TGF-β) and IL-13. Therefore therapeutic strategies designed to overcome these inhibitory immunosuppressive networks may provide an opportunity to enhance anti-tumor immunity by promoting the generation of T cell priming in combination with RT.
Emerging biological insights and target identification of some of the important immune checkpoints that control regulation of anti-tumor immunity have led to the development of an increasing number of novel immunomodulatory agents. These new therapeutics can be broadly divided into either agonists or immune stimulating receptors (co-stimulatory receptors) eg CD40, OX40,CD137 /4-1BB or antagonists of immune suppressor molecules (co-inhibitory molecules) eg CTLA4, PD-1,PD-L1, LAG-3,Tim-3 that are able to overcome the down regulation of anti-tumor immunity. Most recent clinical progress has been with immune “check-point inhibitors”. Proof of principle was initially demonstrated with anti- CTLA-4 monoclonal antibodies (mAb) and more recently with anti-PD-1 and anti-PDL1 checkpoint inhibitors leading to durable anti-tumor immune responses in a broad range of cancers including melanoma, renal cell and non-small-cell lung cancer. Although encouraging, clinical responses were observed, this was only in the minority of patients and it is likely that combination therapy approaches will be required to improve response rates to increase response rates for the majority. Combinations of RT and immunomodulatory agents are attractive, given the local anti-tumor efficacy of RT and lack of systemic immunosuppression that is commonly seen with cytotoxic chemotherapy and other systemic agents. The biological premise is that RT initiates local tumour “immunogenic cell death” leading to local immune response that will be augmented by immunomodulatory agents leading to systemic anti-tumor immunity and greater tumor control. Preclinical studies have demonstrated that the anti-tumor immune responses generated by RT can be enhanced through combination with a range of immunomodulatory agents such as immune agonists such as anti-CD40, Toll Like Receptors (TLR), and immune checkpoints inhibitors such anti-CTLA-4, anti-PD1. Understanding the effect of RT on the local TME and using immunomodulatory agents to overcome the immunosuppression within the TME, are key to making further progress. Recent data has demonstrated that fractionated RT leads to local T-cell activation and production of IFNγ which drives adaptive resistance through the PD-1/PD-L1 axis. RT leads to increases in PD-L1 expression on both tumor cells and MDSC within the irradiated tumor. Concurrent treatment with RT and anti-PD-1 mAb overcomes this local immunosuppression facilitating systemic anti-tumor immunity capable of mediating the systemic tumor regression. Dual immune checkpoint inhibitor combinations with RT are likely to be important in more durable remissions. In a melanoma model the optimal anti-tumor response required RT, anti-CTLA-4 and anti-PD-L1/PD-1. Anti-CTLA-4 was found to predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. RT was found to enhance the diversity of the T-cell receptor (TCR) repertoire of intra-tumoral T cells. Together, anti-CTLA-4 was found to promote the expansion of T cells, while RT appeared to increase and define the TCR repertoire of the expanded peripheral clones. The addition of PD-L1 blockade appeared to reverse the T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion, with the triple combination leading to increased durable anti-tumor responses.
The translation of immunomodulation from scientific discovery to effective clinical anti-cancer therapeutics has been considerable over the past decade. RT and immunmodulatory combinations offer great potential to improve outcomes further if the appropriate translational research and well-designed clinical trials are performed. In order to increase the number of responses in the majority of patients across many tumor types further investigation is required to fully understand the potential underlying mechanisms of resistance is required.
In the palliative setting in metastatic disease RT can be used an “immunogenic hub” with local tumor cell death enhancing systemic immune responses with immunomodulatory agents. Further research is required to inform clinical translation including the optimal radiation dose and fraction size, which is likely to be tumor specific, and most importantly the optimal scheduling of RT and immunotherapy. The future however appears extremely promising to potentially convert RT from a local treatment to a highly effective systemic therapy when used in combination with immunomodulatory agents
Citation Format: Tim M. Illidge. The interplay of radiotherapy with the tumour microenvironment: Novel opportunities to overcome adaptive resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY31-02.