Impact of immune infiltration signatures on prognosis in endometrial carcinoma is dependent on the underlying molecular subtype

Objectives: Increased numbers of tumor infiltrating lymphocytes (TIL) in endometrial cancer (EC) are associated with improved survival, but it is unclear how this prognostic significance relates to the underlying EC molecular subtype. In this explorative hypothesis-generating study, we sought to define the immune signatures associated with the molecular subtypes of EC (i.e., POLE-mutated, microsatellite unstable (MSI-high), copy number (CN)-low, and CN-high) and to determine their correlation with patient outcomes.

Methods: RNA-sequencing and molecular subtype data of 232 primary ECs were obtained from The Cancer Genome Atlas. Deconvolution of bulk gene expression data was performed using single sample Gene Set Enrichment Analysis (ssGSEA) and Cell type Identification By Estimating Relative Subsets Of known RNA Transcripts (CIBERSORT). The association of the resultant immune signatures with overall survival was determined across molecular subtypes.

Results: Statistically significant differences in enrichment were identified in 16/30 and 6/23 immune gene sets by ssGSEA and CIBERSORT, respectively. Signature of CD8+ cells in ECs of CN-high molecular subtype was associated with improved overall survival by ssGSEA (p = 0.0108), while CD8 signatures did not appear to be prognostic in MSI-high (p = 0.74) or CN-low EC molecular subtypes (p = 0.793). Of all molecular subtypes, CN-high ECs exhibited the lowest levels of CD8+ T cell infiltration. Consistent with antigen-induced T cell activation and exhaustion, enrichment for immunomodulatory receptors was predominantly observed in ECs of MSI-high and POLE-mutated molecular subtypes.

Conclusions: Deconvolution of bulk gene expression data can be used to identify populations of immune infiltrated endometrial cancers with improved survival. These data support the existence of unique mechanisms of immune resistance within molecular subgroups of the disease.