Over the past 15 years, the term 'immunotherapy' in the field of skin cancer has taken on a renewed significance, marked by the emergence of more targeted therapies modulating the behaviour and phenotype of various immune subsets. Hence, the characterization of new skin immunosuppressive populations and the development of novel therapeutic approaches are pivotal in expanding our arsenal to combat skin cancer.
Double-positive CD4/CD8αβ (DPαβ) T cells are prevalent in peripheral tissues and increase in numbers during cancer development. However, their function remains under debate. We have developed a method to isolate these cells with high purity, by which we confirmed that DPαβ T cells originate from tissue-seeded CD4+ T cells. Notably, single-cell sequencing revealed that 20% of DPαβ T cells expressed FOXP3, suggesting an immunosuppressive phenotype akin to CD4+ T regulatory cells. In fact, in contact hypersensitivity assays, activated DPαβ T cells were able to significantly reduce skin CD8+ T cell-mediated response, affirming their immunosuppressive nature.
Immune checkpoint inhibitors (ICI), such as anti-programmed cell death-1 (PD-1), have revolutionized the treatment of solid tumours. Unfortunately, less than 20% of metastatic/recurrent cutaneous Squamous Cell Carcinoma (cSCC) patients benefit from anti-PD-1 ICI. To enhance treatment responses, our clinical and academic team led the Australian-first MSD-sponsored Phase 2 study DesQuamate. This study explored the benefits of neoadjuvant anti-PD-1 therapy in patients diagnosed with Stage II-IV (M0) resectable cSCC. The results demonstrate that 67% of the patients achieved either pathology or clinical complete response with no recurrence with a minimum follow-up of 6 months. Our preliminary spatial transcriptomic analysis of tumour samples revealed elevated levels of myeloid suppressive cells and higher PDL-1 levels in non-responders than in responders. Additionally, non-responder tumors exhibit a progressive shift towards an epithelial-mesenchymal transition phenotype (EMT), which is notably more drug-resistant.
Our findings emphasize the significance of recognizing newly characterized DPαβ T cells as a pertinent therapeutic target. Furthermore, they highlight the critical importance of timing in modulating the immune response.
Wei Yang Kong*1, Rahul Ladwa*2,3, Jenny HJ Lee4, Sandro V Porceddu5, Margaret Louise McGrath2, Caroline Cooper2,3, Howard Liu2, Ruta Gupta6, Claire Cuscaden2, Michelle K. Nottage2, Jonathan Clark4, Dieu Le2, Marketa Pauley6, Brett Gordon Maxwell Hughes6, Benedict J Panizza2,3, James W. Wells1, Jazmina L. Gonzalez Cruz1.