Aims:
Keratinocyte Cancers (KC), including invasive cutaneous squamous cell carcinoma (cSCC), intraepidermal squamous cell carcinoma (IEC) and basal cell carcinoma (BCC) occur at disproportionately higher levels in immunosuppressed patients including organ transplant recipients (OTRs). KCs are more likely to recur and metastasise in OTRs and are a major cause of mortality in this growing population. There is limited understanding of the biology of skin cancers from OTRs. The tumour microenvironment (TME) influences the behaviour of tumours, and understanding its composition can aid in prognostication and treatment. The objective of this study was to characterise the TME of KCs from OTRs, and to correlate findings with clinicopathologic parameters.
Methods:
The composition of the TME from 74 tumours that developed in OTRs who were participants in the phase 3 ONTRANS clinical trial investigating the effect of oral nicotinamide on KC incidence in OTRs was examined. The TME was characterised using a novel high-dimensional tissue imaging technology, Imaging Mass Cytometry (IMC). Formalin fixed paraffin embedded tissues were simultaneously stained with 40 antibodies enabling identification of hundreds of cell populations. Unbiased clustering and spatial analysis were performed to identify spatial distributions and cell interactions.
Results:
Tumours from OTRs on oral nicotinamide treatment have depleted levels of PD1+ B cells compared to placebo (p = 0.005). cSCC had higher abundances of PD1+ and PDL1+ B cells compared to BCC (p = 0.02, 0.002), and were enriched in CD103+ CD8+ T cells (p = 0.045). Tumours from the head and neck demonstrated an immunosuppressive TME compared to tumours from other body sites; with reduced levels of CD4+ and CD8+ TEMRA cells (p = 0.02, p= 0.03), reduced levels of CD4+ and CD8+ T effector memory cells (p = 0.02, p = 0.02) and increased CD8+ T naïve cells (p=0.008). Head and neck tumours had a higher tumour proliferative index (p = 0.04).
Discussion
Nicotinamide may deplete tumour promoting, immunosuppressive B cells in the TME. Immunosuppressive B cells, enriched in cSCC compared to BCC, may contribute to the more aggressive clinical behaviour demonstrated by cSCC. Tumours from the head and neck, a site of high recurrence and metastasis, are characterised by an immunosuppressive TME favouring immune escape and tumour survival.
Conclusion:
We provide an in-depth characterisation of the TME of KC from OTRs using a high-dimensional spatial pathology pipeline. TME composition affects clinical behaviour of KCs in OTRs.