Emerging biomarkers for the combination of radiotherapy and immune checkpoint blockers

Abstract

Over the past few years, multiple immune checkpoint blockers (ICBs) have achieved unprecedented clinical success and have been approved by regulatory agencies for the treatment of an increasing number of malignancies. However, only a limited fraction of patients responds to ICBs employed as a standalone intervention, calling for the development of combinatorial regimens. Radiation therapy (RT) stands out as a very promising candidate for this purpose. Indeed, RT mediates antineoplastic effects not only by cytotoxic and cytostatic mechanisms, but also by modulating immunological functions, both locally (within the irradiated field) and systemically. As combinatorial regimens involving RT and ICBs are being developed and clinically tested at an accelerating pace, it is paramount to identify biomarkers that reliably predict the likelihood of individual patients to respond. Here, we discuss emerging biomarkers that may potentially predict the response of cancer patients to RT plus ICBs.

Relationship between pneumonitis induced by immune checkpoint inhibitors and the underlying parenchymal status: a retrospective study

“…Although the pathogenesis of IP is largely unknown, immune dysregulation likely plays a role, as pathological specimens are typically characterised by lymphocyte infiltration [20]. It can be hypothesised that during immunotherapy, lung homeostasis is altered and an autoimmune reaction is triggered [21,22]. In this setting, it is conceivable that the predominant reaction is seen firstly where the lymphocytes are pooled, such as around tumoral lesions or within the RT field, and it could then diffuse to the surrounding areas and, in some cases, to distant regions.…”

“…In addition to its antitumoural effects, RT promotes an immune, mainly T-cell-mediated, response known as "in situ vaccination", which plays an important role in the outcome of RT [21,22,24]. This immune system activation is not restricted to the RT field but also induces a systemic, tumour-specific immune response outside the RT field due to immunogenic cell death.…”

Enhancing the efficacy of immunotherapy using radiotherapy

“…131,132 Recently, the expression of the cGAS-STING IFN type I synthesis pathway prior to starting treatment has been suggested as a biomarker to determine patients who will obtain durable responses from radiotherapy and ICPB combination in colorectal cancer. 133,134 In another cohort, increased HIF-1a and vascular endothelial growth factor-A anticipated poor responses to radiotherapy because of induction of Treg and MDSC migration to the TME. 135 Overall, although these biomarkers may provide some indication of the likelihood of response, they have low specificity, and more research is warranted to validate candidate biomarkers, to broaden our understanding of the impacts of radiotherapy on the immune systemand thus optimise combinations of radiotherapy and ICPB.…”

Radiation therapy and the innate immune response: Clinical implications for immunotherapy approaches

“…In that regard, the potential use of the composition of the immune response as tumour progression biomarker needs further discussion. The term immunoscore refers mainly to the degree of tumour‐infiltrating lymphocytes) and its prognostic/diagnostic potential after treatment 105–107 . However, fewer advances have been done on the myeloid lineage 108,109 and its role remains poorly understood, particularly after RT treatment and remarks the need for extensive research.…”