OmniSeq, Inc., Buffalo, NY
Antonios Papanicolau-Sengos, Sarabjot Pabla, Grace K. Dy, Marc S. Ernstoff, Igor Puzanov, Jeffrey M. Conroy, Mary Nesline, Sean T. Glenn, Blake Burgher, Jonathan Andreas, Vincent Giamo, Maochun Qin, Felicia L. Lenzo, Mark Gardner, Carl Morrison
Background: The association between neoplasm mutational and immune profiles has not been well-characterized. Methods: We collected 26 lung cancer formalin-fixed paraffin embedded (FFPE) samples which had been tested with a comprehensive mutation profile to detect clinically actionable mutations, and a comprehensive immune gene expression profile, which interrogates PD-L1 immunohistochemistry (IHC), PD-L1/2 copy number, CD3/CD8 IHC, microsatellite instability status, mutational burden, and the expression profile of 54 immune-related genes. The ranking of gene expression and 7 immune phenotypes was compared to a reference population. Six cases were positive for an activating KRAS mutation and 2 cases were positive for an activating EGFR mutation. Principal component analysis was performed to determine the association of EGFR/KRAS mutations with the measured immune landscape. Results: The proinflammatory immune phenotype was significantly correlated with KRAS mutation positive samples (first principal component, R squared = 0.53, p < 0.05). Similarly, CD38 expression was correlated with KRAS mutation (R squared = 0.47, p < 0.05). CD137, KLRD1, and DDX58 expression was significantly correlated with EGFR positive samples (second principal component, R squared = 0.47, 0.37, 0.35 respectively, p < 0.05 in all cases). Unsupervised hierarchical clustering of the samples resulted in three distinct clusters, EGFR positive, KRAS positive, and EGFR negative/KRAS negative. In the KRAS positive cluster, high proinflammatory immune phenotype, VISTA moderate expression, presence of CD3/CD8 tumor infiltrating lymphocytes (TILs), and low KLRD1 were overrepresented (p < 0.05), while low VISTA and proinflammatory moderate immune phenotype were significantly underrepresented (p < 0.05). In the EGFR positive cluster DDX58 high, very low TILs, and very low CD8 were significantly (p < 0.05) overrepresented. Conclusions: KRAS mutation positivity is significantly associated with a proinflammatrory immune phenotype and CD3/CD8 infiltration. KRAS positive, EGFR positive, and KRAS/EGFR negative clusters are immunophenotypically distinct. A higher number of specimens is necessary to verify and expand these findings.
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