Molecular and genetic properties of tumors associated with local immune cytolytic activity

By Michael S. Rooney, S. Shukla, Catherine J. Wu, G. Getz, Nir Hacohen. Cell, 2015

3,255 citations recorded by the source corpus.

Summary How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic datasets 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.

Subfields: Immunology, Oncology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/a1d77f76e7c269a69c706105f7ce5f1a71c42d59

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In Immunology

In Oncology

In Radiology, Nuclear Medicine and Imaging

Citations in the corpus

Genomic features of response to combination immunotherapy in patients with advanced non-small cell lung cancer (2018, result): “TMB and computationally predicted neoantigen burden were highly correlated (Spearman r 0.92, p < 0.0001; Figure S2G), consistent with this characteristically proportional relationship (Rooney et al., 2015; Van Allen et al., 2015).”
Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy (2016, positive): “A foundational principle of tumor immunology is that cancer cells can be eliminated by host cytotoxic CD8+ T cells (Schreiber et al., 2011; Gajewski et al., 2013; Schumacher and Schreiber, 2015; Rooney et al., 2015).”
Histone Deacetylase Inhibitors as Anticancer Drugs (2017, background): “Several tumor associated antigens have been shown to be epigenetically silenced in malignancies impede immune recognition by cytotoxic T cells and contributing to worse prognosis [124,125].”
Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12 (2018, positive): “Comparison of pre- and post-treatment samples revealed that IL-12 delivery enhanced expression of core cytolytic genes (Rooney et al., 2015) within tumors (Figures 5A and 5B).”
The Immune Landscape of Cancer (2018, background): “C2 was enriched in many of these genes, as well as HLA-A and B and CASP8, which could be immune-evading mechanisms (Rooney et al., 2015).”
Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues (2020, background): “The B cell marker genes included BACH2, BANK1, BLK, BTLA, CD79A, CD79B, FCRL1, FCRL3, HVCN1, and RALGPS2 [12] .”