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

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Jan 17

PMID 25594174

Citations 2091

Authors

Michael S Rooney

Sachet A Shukla

Catherine J Wu

Gad Getz

Nir Hacohen

Affiliations

Soon will be listed here.

Abstract

How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity.

Citing Articles

Proteogenomic Profiling of Treatment-Naïve Metastatic Malignant Melanoma.

Kuras M, Betancourt L, Hong R, Szadai L, Rodriguez J, Horvatovich P Cancers (Basel). 2025; 17(5).

PMID: 40075679 PMC: 11899103. DOI: 10.3390/cancers17050832.

Global Trends in Incidence and Mortality Rates of Endometrial Cancer Among Individuals Aged 55 years and Above From 1990 to 2021: An Analysis of the Global Burden of Disease.

Gao S, Wang J, Li Z, Wang T, Wang J Int J Womens Health. 2025; 17:651-662.

PMID: 40066179 PMC: 11892492. DOI: 10.2147/IJWH.S499435.

Prognostic and Therapeutic Significance of Cancer-Associated Fibroblasts Genes in Osteosarcoma Based on Bulk and Single-Cell RNA Sequencing Data.

Que Y, Ding T, Wang H, Xu S, He P, Shen Q J Cell Mol Med. 2025; 29(5):e70424.

PMID: 40045162 PMC: 11882394. DOI: 10.1111/jcmm.70424.

Multi-omics clustering analysis carries out the molecular-specific subtypes of thyroid carcinoma: implicating for the precise treatment strategies.

Wang Z, Han Q, Hu X, Wang X, Sun R, Huang S Genes Immun. 2025; .

PMID: 40038532 DOI: 10.1038/s41435-025-00322-w.

Immunogenic cell death signature predicts survival and reveals the role of VEGFA + Mast cells in lung adenocarcinoma.

Zhang M, Zhou G, Xu Y, Wei B, Liu Q, Zhang G Sci Rep. 2025; 15(1):7213.

PMID: 40021802 PMC: 11871002. DOI: 10.1038/s41598-025-91401-5.

References

Samuels Y, Ericson K . Oncogenic PI3K and its role in cancer. Curr Opin Oncol. 2005; 18(1):77-82. DOI: 10.1097/01.cco.0000198021.99347.b9. View

Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R . Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005; 353(25):2654-66. DOI: 10.1056/NEJMoa051424. View

Herbst R, Soria J, Kowanetz M, Fine G, Hamid O, Gordon M . Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014; 515(7528):563-7. PMC: 4836193. DOI: 10.1038/nature14011. View

Song J, Kim J, Sun B, Alcala Jr M, Bartlett D, Lee Y . c-Cbl acts as a mediator of Src-induced activation of the PI3K-Akt signal transduction pathway during TRAIL treatment. Cell Signal. 2009; 22(3):377-85. PMC: 2965849. DOI: 10.1016/j.cellsig.2009.10.007. View

Khong H, Restifo N . Natural selection of tumor variants in the generation of "tumor escape" phenotypes. Nat Immunol. 2002; 3(11):999-1005. PMC: 1508168. DOI: 10.1038/ni1102-999. View

Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N . Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003; 9(10):1269-74. DOI: 10.1038/nm934. View

Forrest A, Kawaji H, Rehli M, Baillie J, de Hoon M, Haberle V . A promoter-level mammalian expression atlas. Nature. 2014; 507(7493):462-70. PMC: 4529748. DOI: 10.1038/nature13182. View

Nielsen M, Lundegaard C, Blicher T, Lamberth K, Harndahl M, Justesen S . NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS One. 2007; 2(8):e796. PMC: 1949492. DOI: 10.1371/journal.pone.0000796. View

Lund J, Hsing L, Pham T, Rudensky A . Coordination of early protective immunity to viral infection by regulatory T cells. Science. 2008; 320(5880):1220-4. PMC: 2519146. DOI: 10.1126/science.1155209. View

10.

Tumeh P, Harview C, Yearley J, Shintaku I, Taylor E, Robert L . PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014; 515(7528):568-71. PMC: 4246418. DOI: 10.1038/nature13954. View

11.

Schmitt K, Reichrath J, Roesch A, Meese E, Mayer J . Transcriptional profiling of human endogenous retrovirus group HERV-K(HML-2) loci in melanoma. Genome Biol Evol. 2013; 5(2):307-28. PMC: 3590776. DOI: 10.1093/gbe/evt010. View

12.

Garofalo M, Di Leva G, Romano G, Nuovo G, Suh S, Ngankeu A . RETRACTED: miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009; 16(6):498-509. PMC: 2796583. DOI: 10.1016/j.ccr.2009.10.014. View

13.

Manghera M, Douville R . Endogenous retrovirus-K promoter: a landing strip for inflammatory transcription factors?. Retrovirology. 2013; 10:16. PMC: 3598470. DOI: 10.1186/1742-4690-10-16. View

14.

Lawrence M, Stojanov P, Mermel C, Robinson J, Garraway L, Golub T . Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 2014; 505(7484):495-501. PMC: 4048962. DOI: 10.1038/nature12912. View

15.

Barbie D, Tamayo P, Boehm J, Kim S, Moody S, Dunn I . Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature. 2009; 462(7269):108-12. PMC: 2783335. DOI: 10.1038/nature08460. View

16.

Izeradjene K, Douglas L, Delaney A, Houghton J . Casein kinase II (CK2) enhances death-inducing signaling complex (DISC) activity in TRAIL-induced apoptosis in human colon carcinoma cell lines. Oncogene. 2005; 24(12):2050-8. DOI: 10.1038/sj.onc.1208397. View

17.

Schreiber R, Old L, Smyth M . Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011; 331(6024):1565-70. DOI: 10.1126/science.1203486. View

18.

Boller K, Janssen O, Schuldes H, Tonjes R, Kurth R . Characterization of the antibody response specific for the human endogenous retrovirus HTDV/HERV-K. J Virol. 1997; 71(6):4581-8. PMC: 191680. DOI: 10.1128/JVI.71.6.4581-4588.1997. View

19.

Uderhardt S, Herrmann M, Oskolkova O, Aschermann S, Bicker W, Ipseiz N . 12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance. Immunity. 2012; 36(5):834-46. DOI: 10.1016/j.immuni.2012.03.010. View

20.

Young G, Eksmond U, Salcedo R, Alexopoulou L, Stoye J, Kassiotis G . Resurrection of endogenous retroviruses in antibody-deficient mice. Nature. 2012; 491(7426):774-8. PMC: 3511586. DOI: 10.1038/nature11599. View