Chemotherapy Exposure Increases the Mutational Age of Normal Blood
Chemotherapy exposure increases the risk for therapy-related cancer; however, the mutational consequences of treatment in healthy cells of cancer survivors remain unknown. Bertrums, Rosendahl Huber, de Kanter, and colleagues studied the mutation burden in hematopoietic stem cells of children treated for cancer, revealing an increased treatment-associated mutation burden comparable to the accumulation observed during 16 years of healthy life. This was mostly caused by clock-like processes that are also active during normal aging. Phylogenetic inference of somatic mutations in single cells indicated that most therapy-related myeloid neoplasms originated after the start of treatment and became dominant during or after chemotherapy exposure.
Clostridioides difficile Promotes Colon Tumorigenesis through the TcdB Toxin
Initiation and progression of colorectal cancer (CRC) can be induced through components of the gut microbiome, with protumorigenic organisms still being defined. Drewes, Chen, Markham, and colleagues tested the tumorigenic potential of colonic mucosal slurries derived from patients with CRC and found that colon tumorigenesis was dependent upon the toxigenic Clostridioides difficile bacterial strain and its toxin TcdB. Mechanistically, this toxin induced Wnt/Myc signaling in colonic progenitor cells, reactive oxygen species, and recruitment of activated myeloid cells and IL17-producing cells, suggesting that chronic C. difficile colonization can drive CRC tumor growth.
TIGIT Is a Marker of CD19 CAR-T Cell Dysfunction in Non-Hodgkin Lymphoma
While CAR-T cell therapies directed toward CD19 have been highly successful in the treatment of lymphomas, there are still a large number of patients who exhibit poor responses for unknown reasons. To address this issue, Jackson, Hong, and colleagues generated a single-cell RNA/protein sequencing dataset from serial pre- and postinfusion CAR-T cells administered to patients with lymphoma and identified TIGIT as a marker of poor response and CAR-T cell dysfunction. Moreover, using a mouse model of human lymphoma, the efficacy of CD19 CAR-T cells was improved with coadministration of a TIGIT blocking antibody.
Lysophosphatidic Acid Inhibits Type I Interferons in Ovarian Cancer
Ovarian tumors are refractory to standard treatments and current immunotherapies. Chae and colleagues found that ovarian cancer cells produce copious amounts of lysophosphatidic acid that inhibits expression of type I interferons through tumor-infiltrating myeloid cells. Genetic loss of autotaxin, an enzyme necessary for lysophosphatidic acid generation, rendered ovarian tumors susceptible to interventions that elicit protective responses driven by type I interferon. In human ovarian cancer specimens, expression of a new lysophosphatidic acid–controlled gene signature correlated with poor responses to combined treatment with PD-1 and PARP inhibitors. These findings suggest that lysophosphatidic acid is a key immunosuppressive mediator promoting immunotherapy resistance in ovarian cancer.
Distinct BCL10 Mutation Classes Can Guide Precision Therapy in DLBCL
Aberrant function of the CARD11–BCL10–MALT1 (CBM) complex occurs in B-cell lymphomas. Activating mutations in CARD11 and MALT1 enhance CBM function, but BCL10 mutations, despite being prevalent in diffuse B-cell lymphoma (DLBCL), remain understudied. Xia, David, and colleagues used structure–function approaches to determine two functionally distinct classes of BCL10 mutations: missense mutations in the CARD domain and C-terminal tail truncations. Both conferred resistance to BTK inhibitors, but only BCL10 truncation mutations promoted BCL10 polymerization and potent MALT1 protease activity, leading to MALT1 inhibitor hypersensitivity. Consideration of these mutation classes may therefore guide the selection of precision therapy for patients with DLBCL.
Targeted Degradation of Tumor-Surface PD-L1 Improves MAPK Inhibitor Therapy
MAPK-targeted therapy can recruit antitumor CD8+ T cells to improve efficacy. However, therapy-induced accumulation of tumor cell–surface PD-L1 may attenuate T cells. To test if targeted degradation of tumor cell–surface PD-L1 during MAPK inhibitor therapy improves efficacy, Yang, Wang, and colleagues discovered that the E3 ligase, ITCH, ubiquitinates and internalizes PD-L1 for lysosomal degradation. ITCH gain of function in tumor cells potentiated MAPK inhibitor responses by degrading PD-L1 and enhancing cytolytic CD8+ T cells. A small-molecule ITCH agonist was also identified that improved MAPK inhibitor responses in syngeneic models, paving the way for clinical translation.
Inhibition of IL27 Signaling Activates Anticancer Immunity in the Liver
While the roles of various immune cells have been previously implicated in hepatocellular carcinoma (HCC), the mechanisms controlling anticancer immunity remain poorly understood. Aghayev, Mazitova, Fang, and colleagues identified a pathogenic role for IL27 in liver cancer and demonstrated that genetic or pharmacologic ablation of IL27 cytokine signaling suppressed HCC tumor development in two different models of liver cancer. This was associated with enhanced accumulation and activation of innate cytotoxic cells including natural killer and type 1 innate lymphoid cells. Moreover, higher levels of IL27RA expression and circulating IL27 were associated with poor survival in patients with HCC.
Stress Granules Drive Obesity-Associated Pancreatic Cancer through SRPK2
Despite significant epidemiologic evidence linking obesity to increased cancer incidence and mortality, the mechanistic determinants of this phenomenon remain understudied. Fonteneau and colleagues determined that obesity promotes pancreatic ductal adenocarcinoma (PDAC) through the upregulation of stress granules (SG), which are stress-adaptive biomolecular condensates. PDAC arising in diet-induced and genetic mouse models of obesity showed enhanced SG levels, with SG upregulation in obesity-associated PDAC being mediated by SRSF protein kinase 2 (SRPK2). Obesity-associated hyperactivation of the IGF1/IGF1R/S6K axis promotes the phosphorylation of SRPK2 and, consequently, SG upregulation, while targeting IGF1/IGF1R/S6K specifically inhibits SGs and growth of obesity-associated PDAC.