In This Issue

See article, p. 591.

The somatic mutation landscape of lung cancer varies among populations, including in Latin America, but whether differences in ancestry or environmental exposures explain the disparities is unknown. Carrot-Zhang and colleagues investigated this using sequencing data from 1,153 lung cancers from patients (43% of whom did not smoke) from Mexico and Colombia, finding that Native American ancestry had a substantial impact on tumors' somatic mutation profiles. For example, oncogenic EGFR mutations were more common in individuals with greater Native American ancestry. This work suggests that germline differences rather than environmental exposures account for the varying somatic mutation patterns in these populations.

See article, p. 599.

With the advent of immunotherapies that harness tumor cell killing by T cells, such as chimeric antigen receptor (CAR) T-cell treatments, understanding the mechanisms underlying T cells' antitumor activity has become more important than ever. Upadhyay and colleagues discovered a previously unknown role for apoptotic FAS–FASL signaling in T cell–mediated cytotoxicity against tumor cells in vivo. FAS–FASL signaling enabled CD8⁺ T cells to kill antigen-negative “bystander” tumor cells, potentially explaining how CAR T-cell treatments—which are directed to their targets by the presence of a specific antigen—are capable of eradicating heterogeneous tumors that inherently harbor some antigen-negative cells.

See article, p. 614.

Treatment with immune checkpoint inhibitors (ICI) can trigger autoimmune myocarditis that is often fatal, and the risk increases with combination blockade of CTLA4 and PD-1 or PD-L1. Wei, Meijers, and colleagues generated Ctla4^+/− Pdcd1^−/− mice that recapitulated the features of ICI-induced myocarditis in humans, including myocardial infiltration by T cells and macrophages. These abnormalities were not observed in Ctla4^+/+ Pdcd1^−/− mice, suggesting that a gene dosage-dependent interaction between Ctla4 and Pdcd1 underlies the increased frequency of myocarditis seen with combination ICI therapy. In this model, many of the ICI myocarditis–like effects were prevented by treatment with abatacept (recombinant CTLA4–Ig) to block T-cell costimulation. A patient case series also provided early support for this mechanistically informed treatment.

See article, p. 626.

In acute myeloid leukemia (AML), as with many other malignancies, the prognosis for Black patients is worse than that for white patients on average. Bhatnagar and colleagues found that the survival disparity was most substantial in patients under 60 years of age, and this trend remained significant after adjusting for socioeconomic status and molecular characteristics. Of note, NPM1 mutations—which are associated with better prognosis in other groups when they are present without co-occurring FLT internal tandem duplication mutations—did not confer reduced risk in younger Black patients. This work highlights the importance of the genetic underpinnings of some racial cancer disparities.

See article, p. 638.

The study and treatment of pancreatic ductal adenocarcinoma (PDAC) is complicated by interpatient heterogeneity that cannot be explained by mutational differences alone. To investigate this, Espinet and colleagues performed transcriptomic and DNA methylomic analyses on epithelial cells from human PDACs and normal pancreata. This revealed the existence of an aggressive subgroup characterized by hypomethylation of repetitive elements, yielding higher expression of endogenous retroviral elements and sensors of double-stranded RNA and leading to activation of an IFN-linked transcriptional program. These low-methylation PDACs and their less aggressive high-methylation counterparts preserved cell-of-origin traits representing ductal and acinar lineages, respectively. This study provides insight into a previously uncharacterized PDAC classifier.

See article, p. 660.

The existence of several transcriptionally defined subtypes of pancreatic ductal adenocarcinoma (PDAC) is established, but it is not known what factors influence the subtype a PDAC will adopt. To investigate this, Flowers and colleagues used genetically engineered mouse models in which PDAC development occurred in adulthood, mimicking the human disease course. This work revealed that oncogenic Kras mutation combined with Trp53 deletion or inactivating point mutations could lead to PDAC originating from ductal or acinar cells. Acinar cell–derived and ductal cell–derived PDACs were transcriptionally distinct, and comparison with human PDACs revealed a relationship between cell of origin–based transcriptional signature and molecular subtype.

See article, p. 678.

Some data suggest that premetastatic intervention via eradicating melanoma circulating tumor cells (CTC) holds promise. Hong, Roh, and colleagues found that, to avoid ferroptotic death mediated by excess reactive oxygen species while in blood, CTCs upregulated lipogenic pathways controlled by SREBF2 and iron homeostatic proteins, including transferrin. Knockdown of the gene encoding transferrin impaired tumor formation by CTCs in mice, and the tumor-forming potential of these CTCs was restored by ferrostatin-1 and vitamin E. Prospective patient data showed that high expression of SREBF2-regulated genes and transferrin in melanoma CTCs correlated with poor prognosis, supporting the potential clinical relevance of these findings.

See article, p. 696.

Personalized neoantigen vaccines for cancer have shown promise in early trials; however, perplexing results—such as lack of response to most in silico–predicted neoantigens—have also arisen. Lam and colleagues developed ATLAS, an ex vivo bioassay to detect antigens that either stimulate or inhibit T cell–mediated immune control tumor control. In mice, vaccination with ATLAS-identified stimulatory neoantigens caused antitumor immune responses, but inclusion of even a single inhibitory ATLAS-identified antigen abolished this effect, sometimes increasing the tumor growth rate. Validating the potential of this approach, a planned interim analysis of a clinical trial showed that ALTAS-identified antigens stimulated immune responses in patients.

See article, p. 714.

The clinical benefit of type I RAF kinase inhibitors that bind the active conformation of the enzyme has been improved with the combination of allosteric MEK inhibitors in BRAF^V600-mutant melanoma, but resistance caused by MAPK pathway reactivation remains a problem. Hong, Piva, Lu, and colleagues showed that type II inhibitors that bind the inactive conformation of RAF could prevent and overcome acquired resistance when used in combination with allosteric MEK inhibitors in BRAF-, NF1-, NRAS-, and KRAS-mutant models. This combination resulted in tumor cell–intrinsic sequestration of MEK in RAF complexes, which reduced MEK homodimerization and uncoupled MEK from ERK to prevent MAPK pathway reactivation, and tumor cell–extrinsic CD8⁺ T cell–mediated tumor regression.

See article, p. 736.

Pancreatic ductal adenocarcinomas (PDAC) rarely respond to immunotherapy due to their generally immunosuppressive tumor microenvironment (TME). To identify tumor cell–intrinsic factors that modulate antitumor immunity, Li, Yuan and colleagues performed an in vivo CRISPR–Cas9 screen in a mouse model recapitulating the heterogeneous immune TME of human PDAC. Loss of the histone H3K9me2 lysine demethylase gene Kdm3a was associated with an increase in tumor-infiltrating T cells and dendritic cells, a decrease in immunosuppressive myeloid cells, and a marked increase in response to immunotherapy. Transcriptomic and epigenomic analyses implicated EGFR as a key KDM3A target, and knockout or inhibition of EGFR rewired the immune TME from a non–T-cell-inflamed state to a T-cell-inflamed state. EGFR inhibition also increased the efficacy of combined CD40 agonist, PD-1 blockade, and CTLA4 blockade.

See article, p. 754.

Our understanding of cell states and fate transitions has been limited by the lack of tools to genetically trace individual cell populations. Schmitt, Company, Dramaretska, and colleagues developed a genetic tracer method wherein cis-regulatory elements of genes specifically activated in glioblastoma subtypes were identified and joined together to create a synthetic locus control region regulating subtype-specific expression of a fluorescent reporter. This methodology revealed heterogeneity and hierarchies within the glioblastoma subtypes and showed that while the proneural subtype identity was fixed, the mesenchymal subtype identity was far more adaptive. The phenotypic changes induced by tumor-immune cell cross-talk or different therapies could also be evaluated. Importantly, this synthetic genetic tracing approach is scalable and can be readily applied to study cellular homeostasis in other cancer types.

See article, p. 778.

The lack of recurring genetic alterations in Hippo pathway genes makes identifying tumors that are dependent on deregulated Hippo signaling challenging. Pham, Hagenbeek, Lee, and colleagues identified a set of consensus gene clusters that were downregulated upon knockdown of YAP1 or WWTR1 (also known as TAZ) and used a machine learning computational model to predict YAP1/WWTR1 dependency in a broad set of cell lines. Of note, one of the gene clusters co-expressed with YAP1/WWTR1 was strongly associated with MAPK pathway activation, and a small-molecule drug screen for compounds having the greatest effect on cell viability in combination with YAP1 knockdown identified multiple MEK inhibitors. This lineage-independent, unbiased approach provides a framework for characterizing signaling pathway dependency and cross-talk to identify potential treatment combinations.

In This Issue is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details.