Pan-cancer immunogenomic analyses reveal genotype–immunophenotype relationships and predictors of response to checkpoint blockade
Data from 20 solid tumors in The Cancer Genome Atlas were analyzed for metagene signatures, identifying immune cells and the genetic signatures of the tumors, with the resultant data becoming a public-access resource called The Cancer Immunome Atlas. Responses to immunotherapy could be predicted based on derived immunophenoscores, and results have been validated using fresh cohorts.
NLRC3 is an inhibitory sensor of PI3K–mTOR pathways in cancer
Cytoplasmic sensors alert the immune system of infection, but some, like NLRC3, inhibit innate signaling. NLRC3 expression is low in human colorectal cancer, and mice lacking NLRC3 are very susceptible to colitis and colorectal tumorigenesis. NLRC3 inhibits the mTOR pathway, blocking proliferation and preventing stem cell–derived organoid formation.
Deubiquitination and stabilization of PD-L1 by CSN5
The tumor microenvironment induces expression of PD-L1, but it is unclear how expression is maintained. CSN5, a member of the COP9 signalosome complex, is known to play a key cell-intrinsic role in cancer progression. Expression can be induced by TNF, and this leads to stabilization of PD-L1 through the deubiquitination activity of CSN5, which further promotes tumor progression by interfering with responses to checkpoint blockade.
What does PD-L1 positive or negative mean?
PD-L1 expression has been proposed as a biomarker to predict responses to immunotherapies. However, the amount of PD-L1 reflects both induced, by tumor-infiltrating T cells, and constitutive, based on cell-intrinsic genetic factors, expression. The use of PD-L1 expression to predict response to immunotherapy must consider the presence of T cells.
Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions
Acute myeloid leukemia patients often respond to first-line chemotherapy but then relapse with resistant disease. Vaccination of 17 patients with autologous DCs fused to their AML cells induced detectable T-cell responses, and 12 patients have remained disease-free after 57 months of follow-up.
Dissecting biological control circuits by pairing CRISPR and single-cell RNA-seq technologies
Two massively parallel techniques combining genomic perturbation and single-cell RNA-seq, one deemed CRISP-seq and the other Perturb-seq, have been developed to probe complex phenotypes. Jaitin et al. used CRISP-seq to probe the networks participating in myeloid cell differentiation and their responses to pathogens. Dixit et al. identified gene targets and networks with Perturb-seq that are involved in immune activation and regulation of differentiation.