Researchers have found new drivers of cutaneous T cell lymphoma (CTCL). Also, they show that deletion of PD-1 is associated with worse clinical outcomes.
CTCL is a collection of heterogeneous cancers arising in T cells, primarily in the skin. Mycosis fungoides (MF) and Sezary syndrome (SS) constitute around 60% and 5% cases of all CTCLs, respectively. The observed heterogeneity could be a result of unique genetic alterations which distinguish the CTCL subtypes from each other. Earlier studies using older technologies have investigated only a few subtypes of CTCL, limiting our knowledge about this deadly disease.
A recent study by Park et al. has addressed the question of CTCL heterogeneity using high throughput approaches such as whole genome and whole-exome sequencing. They sequenced 95 CTCL tumour samples and integrated their data with published results from 203 tumours. A high number of samples (more than 300) representing the disease heterogeneity in terms of different subtypes, stages, and disease outcomes helped the researches to identify putative drivers of CTCL.
A collective analysis of sequencing data from this set of CTCL tumours revealed 86 putative driver genes, of which 19 genes have never been associated with this disease. Additionaly, two of these mutations have never been associated with any known cancer. The majority of these genes belonged to biological pathways involved in T cell receptor signalling, cytokine signalling and T cell differentiation.
The most important finding of these analyses was the association between PD-1 loss and tumour aggressiveness, resulting in poor outcomes. These results are in line with earlier observations with PD1 immunotherapy and CTCL: while the majority of patients benefit from PD-1 immunotherapy treatment, some patients suffering from other cancers eventually developed CTCL.
These results highlight that PD-1 immunotherapy may not work with all patients. The treatment strategy should be formulated based on the genomic profile of the individual, and different immunotherapies could be used for each subset of patients.
In conclusion, the study by Park et al. identified unique genetic signatures which could help in classifying subtypes of CTCLs, and thus help in the formulation of focussed treatment options for patients.
Park J, Daniels J, Wartewig T, Ringbloom KG, Martinez-Escala ME, Choi S, et al. Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity. Blood. 2021 Oct;138(14):1225–36.