Combination radiotherapy and immunotherapy: effects on the immune landscape of oesophageal adenocarcinoma and the multimodal therapeutic paradigm
Citation:
Noel Edward Donlon, 'Combination radiotherapy and immunotherapy: effects on the immune landscape of oesophageal adenocarcinoma and the multimodal therapeutic paradigm'. Trinity College Dublin. School of Medicine. Discipline of Surgery. 2022.Download Item:
Abstract:
The incidence of cancer of the oesophagus and the gastro-oesophageal junction (GEJ) has increased exponentially in the western world over the last half century. Oesophageal adenocarcinoma (OAC) is now the dominant subtype, heavily influenced by western diets and obesity. Despite advances in the multimodal therapeutic strategies to treat the disease, the overall survival remains poor, primarily due to its indolent nature and consequently metastatic or inoperable disease at presentation. For early-stage disease, there are new endotherapies obviating the need for resection, which carries significant morbidities and mortality. However, in locally advanced disease, neoadjuvant chemo(radio)therapy is the gold standard of treatment in the form of FLOT chemotherapy or CROSS chemoradiotherapy. The response rates remain quite poor with suboptimal pathological responses to these current standards of treatment.
The current work highlights that oesophageal adenocarcinoma is an immunogenic cancer and also suggests the potential synergistic effects between radiation and immunotherapy as a viable and realistic treatment option for oesophageal adenocarcinoma in the curative setting. Furthermore, the perioperative immunosuppressive period provides further rationale for use of immune checkpoint blockade (ICB) in conjunction with the current conventional therapies to propagate anti-tumour immunity and shift away from an immunosuppressive milieu.
Radiation at conventional and fractionated dosing induces upregulation of immune checkpoints and significant expression of Damage Associated Molecular Patterns (DAMPs) in vitro and ex vivo, and radiation therapy was demonstrated to reduce the expression of angiogenesis promoters, which is crucial to mitigate the risk of metastatic disease for upper gastrointestinal cancers. Furthermore, the use of immune checkpoint blockade in combination with radiation synergistically reduced viability in radioresistant cells in this study. Further efforts are needed to understand the nature of radiotherapy-induced immune responses.
This body of work demonstrates that the hostile features of the tumour microenvironment of hypoxia and nutrient deprivation induce the upregulation of a range of immune checkpoints proteins, representing therapeutic potential with single or double agent ICBs that target the PD-1 and CTLA-4 axes. There was also a significant upregulation in IFN-γ and IL-12 by T cells as a consequence of radiation, which was significantly higher under conditions of the tumour microenvironment (TME). The cytolytic assay, which represented an in vitro model of T cell killing at the tumour site following radiation, shows promise of the synchronised and potent anti-tumour effect of combining radiation with immune checkpoint blockade, with significantly increased cytolysis evident with ICB and radiation, particularly noted with 4Gy radiation and Pembrolizumab.
This work also highlighted that the TME is more immunosuppressive than the lymph node microenvironment (LNME), and that nodal involvement surpasses both clinical and pathological tumour staging for prognostication purposes, highlighting the pivotal role of the tumour draining lymph node in OAC pathogenesis. There was also observed evidence of the rewiring of the Tumour Draining Lymph Node (TDLN) toward pre-metastatic niche orchestrated perhaps by the neighbouring TME with increases in immune checkpoint expression, a potential therapuetic target in the curative setting.
In the perioperative study, it was highlighted that there was a prevailing Th2-like immunophenotype post-surgery. Therefore, shifting the balance in favour of a Th1-like phenotype would offer a potent therapeutic approach to promote cancer regression and prevent recurrence in the adjuvant setting and could potentially propagate anti-tumour immune responses perioperatively if ICBs were administered in the immediate neoadjuvant setting.
Consequently, with the promising results from the checkmate 577 trial, this body of work paves the way for further studies and appropriate trial design for the use of ICBs in the multimodal treatment of locally advanced disease in the neoadjuvant, adjuvant and curative setting and warrants further interrogation.
Sponsor
Grant Number
CROSS Charity
RCN: 15364
Author: Donlon, Noel Edward
Advisor:
Lysaght, JoanneReynolds, John V
Qualification name:
Doctor of PhilosophyType of material:
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