Molecular and Genetic Properties of Tumors Associated with Local Immune Cytolytic Activity

· by Xin He · Read in about 2 min · (217 words) ·

By Rooney and Hacohen, Cell, 2015.

Cytolytic activity (CYT)

Measuring cytolytic activity (CYT): using granzyme and perforin levels. CYT activity varies across tumor types: in some tumors, e.g. kidney and cervical cancer, strong induction; but in others, e.g. breast cancer, no.

Correlated genes with CYT: other genes that are markers of CYT activity; also positive correlation with genes usually not expressed in CTLs and NK cells, some are immunosuppresive molecules. Explanation: CYT induces tumor expression of immunosuppressive genes.

Neoantigen load: CYTs are positively correlated with mutation load and neoantigen load. Also find depletion of neoantigen in colorecetal and kidney cancer, comparing with synonymous mutations. CYT also correlates with virus, ERVs and ecotopic gene expression (cancer testis genes).

Genetics of CYT

Mutations associated with CYT: regression controlling for tumor type and background mutation rates. 35 genes, except TP53, all positive correlation, i.e. higher mutations in CYT active tumors. Genes are involved in (1) Antigen presentation: B2M and MHC I. (2) Escape: CASP8. (3) CT antigens. (4) Innate immune sensing: DDX3X, ARID2.

CNVs associated with CYT: PDL1/L2, amplification positively associated with CYT. IDO1/2 and ALOX12B/15B (potent immunosuppressor): amplification in low CYT tumors.

Discussion

Model:

  1. Neoantigens, virus/ERVs: triggers CYT.
  2. Emergence of evading subclones: B2M, HLA, CASP8 LoF mutations, and PDL1/L2 upregualtion.
  3. Emergence of suppressive subclones (non-autonamous mechanism): TP53, ALOX, IDO1/2.