An embryonic gene signature is associated with immune exclusion and poor outcome in immunotherapy treated patients

Introduction:

Novel immunotherapies have revolutionized the treatment of advanced melanoma. However, more than 50% of treated patients fail to respond to immunotherapy and the pathways that mediates resistance to immunotherapy are largely unknown.

Material and method:

We conducted RNA sequencing of pre-treatment biopsies from patients that received PD-1 blockade (n=38) or adoptive cell therapy with Tumor Infiltrating Lymphocytes (n=37). All sequenced data was normalized and analyzed with LIMMA package in R.

Results:

Transcriptome comparison between responders (n=45) and non-responders (n=30) revealed 986 genes that were differentially expressed between the groups (FDR<0.25). In concordance with previous reports, the main pathways enriched in responders were pathways related to leukocyte activation, such as antigen presentation and interferon gamma mediated signaling. In non-responders, the main enriched pathways were related to embryonic phenotype. We compiled a gene signature from 41 genes that were significantly upregulated in non-responders and part of the GO embryonic development pathway. Patients with high embryonic gene signature score had reduced progression free survival and overall survival (3 and 6.1 months vs. not reached after median follow-up of 27 months, p<0.0001) in our immunotherapy cohort and reduced overall survival in the TCGA melanoma cohort (20.4 vs. 64.3 months, p<0.0001). Moreover, the embryonic gene signature score was inversely correlated with T cell infiltration score, as assessed by previously validated T cell inflamed gene signature, in both immunotherapy (r_p = -0.55, p<0.0001) and TCGA (r_p = -0.39, p<0.0001) cohorts.

Conclusion:

We suggest that activation of embryonic pathways may contribute to immune exclusion in melanoma, thereby conferring resistance to immunotherapy.