The role of dendritic cells in radiation-induced immune responses

Radiation therapy is one of the three pillars of conventional cancer treatment, recently joined by immunotherapy as the fourth pillar. The history of progress in radiation therapy as a treatment has been predominantly via advances in physics, technology, and imaging (Beyer et al., 2021; Fiorino et al., 2020). This has been combined with careful clinical trials that have established clear parameters where radiation provides a benefit to patients, and where it does not. For this reason, radiation therapy is one of the most data-driven treatment decisions in oncology. While immunotherapy has established itself as an independent cancer treatment, it has become clear that the immune status of patients and their tumors underlies the success and failure of multimodality treatments. For example, as with many cancers, tumor immune infiltrates in pancreatic cancer can be predictive for outcome following conventional surgery and adjuvant chemoradiation therapy (Bernard et al., 2020; Gunderson et al., 2021; Tang et al., 2018). Despite this, pancreatic cancer is poorly responsive to current immunotherapy options (Brahmer et al., 2012; Royal et al., 2010). Novel approaches and combinations provide hope. Yet, despite the importance of immune responses for conventional cancer treatment responses, immune therapies currently have a more limited utility than conventional treatments. Across all cancers, the percentage of patients who were eligible for immunotherapy in the USA increased from less than 2% to more than 40% between 2011 and 2018, with response estimates increasing from less than 1% to over 12% in the same time period (Haslam and Prasad, 2019). These estimations generally match real-world data, with immunotherapy utilization increasing from 3% to 40% between 2011 and 2019 in Ontario, Canada (Raphael et al., 2022). For the purposes of this review it is critical to note that in the Ontario analysis, approximately 67% of the patients that received immunotherapy also received radiation therapy, while approximately 55% of the patients who did not receive immunotherapy received radiation therapy (Raphael et al., 2022). Thus, radiation remains a significant part of the standard of care for cancer patients regardless of whether immunotherapy is provided. A major goal of ongoing research is to optimize this interaction to generate the best immune support for radiation therapy to help cure tumors, and vice-versa. However, the goals of immunotherapy and radiation therapy are sometimes paradoxical given the toxicity of radiation to critical immune cells (Gough and Crittenden, 2022). For many of the patients referenced in the above epidemiologic studies, it is likely that immunotherapy and radiation therapy were given at different times in their treatment course, and there is currently limited clinical data to formally demonstrate synergy between radiation and immunotherapy in patients despite extensive preclinical data and patient anecdotes. This suggests that we have much to learn about optimally translating radiation and immunotherapy combinations to patients.

In classical immunology, the dendritic cell (DC) is the essential link between innate sensing of infection and adaptive T cell responses. Dendritic cells are uniquely able to move antigen from peripheral sites to lymph nodes (LN) (Broz et al., 2014), which is one of the few locations where naïve T cells can meet antigen. Of the array of innate sensors of infection that DC could potentially express, DC are the highest expressors of TLR3 (Miller et al., 2012), which is particularly able to identify the presence of intracellular infectious agents that demand T cells for effective control (Jelinek et al., 2011; Szeles et al., 2015). In addition, DCs are uniquely able to cross present cell associated antigens from other cells on their MHC Class I (Cruz et al., 2017), ensuring that these cells have all of the required tools to sense infection, carry antigen to T cells, and present that antigen to initiate T cell immune responses.

In cancer, DCs are similarly central to generate initial immunity to tumors in preclinical models (Hildner et al., 2008; Medler et al., 2021). Radiation therapy is an effective tool to kill cancer cells within the treatment field, and DCs are well placed to take the released cell-associated antigen to generate T cell responses against cancer-associated antigens. In this review we will discuss the DCs involved in this process, and how they respond to radiation therapy. We also discuss the relative importance of DCs in new versus pre-existing immunity in mice, and by examining how DCs sense innate damage signals in the tumor environment, we explore how to target these cells to improve the immune consequence of radiation therapy in vivo.

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