POLE Proofreading Deficiency Predicts Response to Checkpoint Blockade
Proofreading defects produced from mutations in the DNA polymerase epsilon (POLE) gene contribute to a hypermutated genome that can potentially sensitize tumors to immune checkpoint blockade. Despite this, many POLE-mutant tumors do not demonstrate a robust response to this type of therapy. Rousseau and colleagues conducted a multicenter clinical trial in patients with POLE-mutated solid tumors and showed that only mutations in the DNA binding or catalytic site of the exonuclease domain of POLE contributed to high tumor burden and subsequent increases to T-cell infiltration and response rates to anti–PD-1 therapy, suggesting their use as a biomarker of anti–PD-1 response.
See article, p. 1435.
PRC2 Inhibitors Revert Epigenetic Mechanisms of Leukemia Immune Escape
Escape from the “graft-versus-tumor” effect represents the main driver of leukemia relapses after allogeneic hematopoietic cell transplantation. In up to 40% of cases, the expression of HLA class II molecules is lost from the surface of leukemic cells, without evidence of mutations in these genes or their regulators. By an integrative multiomic approach, Gambacorta and colleagues identified chromatin compaction in immune genes as a main driver of this phenotype and demonstrate that blocking the activity of the Polycomb Repressive Complex 2 (PRC2) can recover HLA class II expression and facilitate T cell–mediated leukemia recognition.
See article, p. 1449.
The Reverse Transcriptase Inhibitor 3TC Targets Virus-like Repeats in CRC
Repetitive sequences in the genome are overexpressed in colorectal cancer (CRC) where they can replicate through retrotransposition, implying an important function for the viral-like mimicry of repeats in cancer progression. Rajurkar, Parikh, Solovyov, and colleagues show the nucleoside reverse transcriptase inhibitor 3TC disrupts the life cycle of repeats in CRC preclinical models, particularly cell lines with mutant p53, a protein linked to direct suppression of repeats. 3TC suppressed reverse transcriptional products, enhanced DNA damage, and diminished invasive behavior in these models. These findings were further translated into a phase II clinical trial of 3TC treatment in p53-mutant CRC.
See article, p. 1462.
A Novel Small-Molecule PD-L1 Inhibitor Restores Antitumor Immunity
Unlike biologics, small-molecule inhibitors may provide advantages including oral dosing, more facile dose titration, as well as the potential for increased tumor biodistribution. Koblish, Wu, Wang, and colleagues report on the discovery and molecular mode of action of the small molecular inhibitor INCB086550, which binds to PD-L1, induces ligand dimerization and cellular internalization, and restores antitumor immunity. These observations of immune activation and efficacy were also demonstrated in early human clinical trials, supporting the concept of using small molecules as a new therapeutic modality for blocking the PD-1/PD-L1 axis.
See article, p. 1482.
Characterization of the KRASG12C Inhibitor JDQ443 Reveals Clinical Activity
The discovery and characterization of JDQ443, a novel, structurally unique, and selective covalent KRASG12C inhibitor was reported by Weiss, Lorthiois, and colleagues. This inhibitor traps KRAS in a GDP-bound state, sparing direct interactions with the KRAS H95 residue. In preclinical models, JDQ443 potently inhibits KRASG12C-dependent signaling and proliferation, including in those with G12C/H95 double mutations, and also demonstrates dose-dependent antitumor activity in KRASG12C-mutated cell- and patient-derived xenografts. Efficacy in preclinical models is AUC-driven and is enhanced in combination with inhibitors of SHP2, MEK1/2, or CDK4/6. Initial clinical experience demonstrates antitumor activity of JDQ443 monotherapy and JDQ443 plus TNO155 (SHP2 inhibitor) in KRASG12C-mutant malignancies.
See article, p. 1500.
Spatial Profiling Defines Features of Melanoma Progression/Immunosuppression
Most studies that investigate immune surveillance in melanoma using histologic imaging or genomic sequencing techniques do not provide insight into the spatial restrictions between tumor and immune cells. Nirmal, Maliga, Vallius, and colleagues sought to address this by analyzing the spatial organization and transcriptomic profiles of the melanoma tumor microenvironment at various disease stages. These studies revealed molecular programs associated with progression as well as the localization of immunosuppressive niches where MHC-II and IDO1 are highly expressed and myeloid cells expressing PD-L1 were in direct contact with PD-1–expressing T cells.
See article, p. 1518.
The Bioinformatics Platform REFLECT Provides Effective Combination Therapies
Current targeted therapies in oncology focus on one individual alteration and have demonstrated limited response in many patients. Blocking multiple pathways has been suggested to be more effective; therefore, Li and colleagues developed the REFLECT resource, which allows for generation of a signature that shows recurrent coalterations in a specific patient cohort and provides potential therapeutic combinations to target these alterations. Validation of this platform in vitro, in vivo, and clinically suggested targetable coalterations in patient cohorts with immunotherapy response markers, DNA repair alterations, and HER2 activation and demonstrated improvement to survival outcomes.
See article, p. 1542.
Histone Deacetylase Inhibition Induces Type I IFN Production in Leukemia
Pharmacologic deregulation of epigenetic modifiers can activate antitumor immune responses. Using models of acute myeloid leukemia, Salmon, Todorovski, and colleagues found that inhibition of histone deacetylases (HDAC) results in leukemia cell differentiation through the activity of type I IFN produced by plasmacytoid dendritic cells. This cross-talk between the effects of HDAC inhibitors (HDACi) on leukemia cells and immune cells was necessary to maximize the antitumor effects of these agents. Based on these findings, a new combination therapy consisting of HDACis and recombinant type I IFN was tested in preclinical models of human and mouse leukemia, demonstrating increased therapeutic efficacy.
See article, p. 1560.
CAF Subtype–Specific IL6 Depletion Improves Response to Therapy
Carcinoma-associated fibroblasts (CAF) are a major component of the pancreatic cancer tumor microenvironment; however, the functions of the different subtypes remain to be fully defined. McAndrews, Chen, Darpolor, and colleagues investigated two different CAF populations, defined by the expression of fibroblast activation protein (FAP) and alpha smooth muscle actin (αSMA), respectively. Each population exhibited unique functions, with survival increasing as a consequence of FAP+ CAF depletion and decreasing with αSMA+ CAF depletion. Additionally, differing roles of CAF populations in mediating therapy response were observed, including differential impacts on T regulatory cells and a demonstration that IL6 depletion in αSMA+ CAFs, but not FAP+ CAFs, improved gemcitabine efficacy.
See article, p. 1580.