Journal
ONCOIMMUNOLOGY
Volume 6, Issue 2, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2016.1264565
Keywords
Checkpoint inhibition; endometrial cancer; high-risk; molecular classification; tumor-infiltrating lymphocytes
Categories
Funding
- Dutch Cancer Society/Alpe d'Huzes [UMCG 2014-6719]
- Dutch Cancer Society Grant [UL2012-5719]
- Jan Kornelis de Cock Stichting
- Clinician Scientist Award from the Academy of Medical Sciences / Health Foundation
- Oxford Cancer Centre, University of Oxford
- Academy of Medical Sciences (AMS) [AMS-CSF4-Church] Funding Source: researchfish
- National Institute for Health Research [NIHR-CS-012-009, CL-2010-13-007] Funding Source: researchfish
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High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated POLE exonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8(+) (90% and 69%), PD-1(+) (73% and 69%) and PD-L1(+) immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8(+) cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.
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