Abstract
PD-1 immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy. Successful PD-1 ICB improves anti-tumour responses of cytotoxic tumour infiltrating lymphocytes (TILs), but efficacy is limited in some patients. Blockade of co-inhibitory receptor PD-1 on TILs counteracts negative co-stimulation within the tumour microenvironment. However, TILs express multiple co-inhibitory receptors. Upregulation of alternative co-inhibitory pathways on TILs could promote tumour-mediated immune suppression, facilitating tumour escape. There is a need to identify and characterize additional co-inhibitory receptors preferentially upregulated following single-pathway blockade that may sustain immune suppression in non-responding tumours. Improved understanding of combined co-inhibitory and co-stimulatory receptor expression as alternative cellular targets is essential for effectiveness of future combination immunotherapies.Using a mouse model of renal carcinoma (RencaHA) and a cohort of melanoma patients, the modulation of immune profiles by lymphocyte subsets after PD-1 ICB was characterised. Furthermore, combined expression of co-inhibitory and co-stimulatory receptors by lymphocyte populations was investigated as potential biomarkers of response to treatment.
PD-1 ICB induced dynamic changes in peripheral and intra-tumoural co-inhibitory and co-stimulatory immune profiles. Additionally, immunosuppressive regulatory T cell (Treg) subsets responded to PD-1 ICB: PD-1 ICB was associated with increased frequency of Treg TILs. Elevated Treg frequency was also detectable in peripheral blood of tumour bearing mice and melanoma patients post-treatment. Significant changes in immune profile of Treg TILs were observed, with reduced expression of PD-1, and increased expression of co-stimulatory receptors OX40 and 4-1BB. Treg TILs from RencaHA tumours were highly proliferative and suppressed CD8⁺ T cell proliferation ex vivo. Ex vivo IL-10 production by Treg was increased after PD-1 ICB.
The expansion of Treg that restrain anti-tumour responses by cytotoxic TILs represents a mechanism by which immune suppression may be maintained, despite PD-1 ICB, reducing treatment efficacy. Selective targeting of intra-tumoural Treg warrants further investigation for development of novel or combined immunotherapies.
| Date of Award | 27 Sept 2022 |
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| Original language | English |
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| Supervisor | Linda Wooldridge (Supervisor), David Morgan (Supervisor) & Christoph Wuelfing (Supervisor) |