Investigating Radiotherapy and Immunotherapy Combinations in Non-Small Cell Lung Cancer

UoM administered thesis: Phd

Abstract

Non-small cell lung cancer (NSCLC) mortality exceeds that of any other cancer worldwide and 5-year survival rates of 10-15% have changed little over the last several decades. Radiotherapy (RT) plays a major role in the management of localised, isolated metastatic, and stage IV NSCLC, in up to 50% of cases. RT has immunomodulatory effects, some of which can be stimulatory and others that may be suppressive. Understanding the interplay of RT immunomodulatory effects and host immune interactions is therefore vital to developing RT-immunotherapy combinations in clinical practice to improve outcome for patients. The immune checkpoint inhibitors (ICIs), anti-PD-1 and anti-PD-L1 have led to improved survival in stage IV and locally advanced NSCLC. However, the majority of patients do not respond to ICIs. Therefore, effective combination therapies that can focus on more than one axis of the immune system may be required to improve anti-tumour control. This PhD has focussed on investigating the immunogenic effects of RT on murine lung cancer cell lines (LL2, KLN-205 and KP475) in vitro and in vivo. Additionally, the combination of the T cell agonist, anti-OX40 with anti-PD-1 was explored in vivo. Lung cancer cell lines were relatively radioresistant in vitro and in vivo, though the KLN-205 model had some initial response in vivo that led to no survival benefit. RT led to reductions in T cells and increases in CD11b+ Ly6G+ neutrophils/granulocytic myeloid-derived suppressor cells (g-MDSCs) in both models. In KLN-205 tumours, chemokines associated with neutrophil chemotaxis dominated the tumour microenvironment (TME), namely CCL2, CXCL1, and CXCL2; furthermore, CXCL1 and CXCL2 were also tumour cell-derived. Ly6G depletion led to improved response to RT in KLN-205-implanted mice. The combination of anti-OX40 and anti-PD-1 resulted in long-term anti-tumour control in KP475 tumour-bearing mice, and mice clearing tumours were resistant to rechallenge; these effects were CD8+-dependent. Responding KP475 tumours were infiltrated by increasing 41BB-expressing CD8+ T cells. Furthermore, KP475 tumour cells expressed higher levels of OX40L at baseline compared to KLN-205 tumours and increased levels of OX40L-expressing macrophages were seen in KP475 tumours following dual immunotherapy treatment, which could further enhance T cell priming. KP475 tumours comprised of higher basal levels of PD-1-expressing T cells and NKCs than KLN-205 tumours. Overall, work here has highlighted how RT may specifically favour the expansion of neutrophil/g-MDSC populations, which may contribute to treatment resistance. These cells and/or tumour-derived neutrophil chemokines represent a critical therapeutic target to improve patient outcomes. Furthermore, in lung cancer tumours with more substantial baseline CD8+ T cell infiltrate and higher levels of PD-1 expressing T cells and NKCs, the addition of anti-OX40 to anti-PD-1 could be an important therapeutic combination to consider in NSCLC patients where mono-therapeutic approaches may not induce durable tumour response.

Details

Original languageEnglish
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Award date1 Aug 2021