Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

Effective treatment options for relapsed or refractory acute lymphoblastic leukemia (ALL) patients are limited. Although BCL2 antiapoptotic family members are critical for ALL, hematologic toxicity has limited the use of anti-BCL-XL agents. The BCL2-specific inhibitor venetoclax is now approved, however, its efficacy is limited in part by its inability to target BCL-XL. Pullarkat and colleagues demonstrated that chemotherapy and venetoclax could be safely combined with low-dose navitoclax, a BCL2/BCL-XL inhibitor, leading to complete remissions in 60% of patients with relapsed or refractory ALL or lymphoblastic lymphoma and allowing 28% of patients to proceed to transplant or CAR-T therapy.Expert Commentary: This study suggests that dual BCL2 pathway inhibition is feasible and efficacious in the clinic.Pullarkat VA, Lacayo NJ, Jabbour E, Rubnitz JE, Bajel A, Laetsch TW, et al. Venetoclax and navitoclax in combination with chemotherapy in patients with relapsed or refractory acute lymphoblastic leukemia and lymphoblastic lymphoma. Cancer Discov 2021;11:1440–53.Drugs targeting chromatin regulators may synergize with immunotherapy. Griffin and colleagues performed a pooled CRISPR-Cas9 knockout screen of 936 genes related to chromatin regulation. SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) was the most strongly depleted target in two syngeneic cancer models. Deletion of SETDB1 improved the sensitivity of these cancers to checkpoint blockade immunotherapy (CBI). Furthermore, SETDB1 was amplified across human cancers, and its amplification was associated with reduced responsiveness to CBI in patients. Mechanistically, SETDB1 silenced large genomic domains containing immune regulatory genes, particularly regions with segmental duplications, which were replete in transposable elements of the long terminal repeat (LTR) family. Many LTRs retained coding potential, generating peptides displayed on MHC class I molecules and recognized by CD8+ T cells. Indeed, depletion of CD8+ T cells or removal of MHCI from tumors impeded the improved control of SETDB1-deficient tumor cells.Expert Commentary: Disruption of the repressive chromatin modifier SETDB1 enhances antitumor immunity by upregulating immunogenic peptides and immune stimulatory genes in cancer cells.Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, et al. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature; Published online May 5, 2021; DOI: 10.1038/s41586-021-03520-4.The Myc oncoprotein engages multiple mechanisms to stimulate transcription elongation by RNA polymerase II (RNAPII) including ubiquitylation. Endres and colleagues found that Myc interacted directly with the polymerase II-associated factor 1 complex (PAF1c), increasing the binding of both proteins to active promoters. PAF1c was transported to RNAPII by the HUWE1 ubiquitin ligase, and this transfer was essential for transcription elongation driven by Myc. Ubiquitylation of histone H2B occurred in response to Myc and HUWE1, which in turn reorganized chromatin to facilitate transcriptional elongation and double-strand break repair. Upon depletion of PAF1c, double-strand breaks from transcription accumulated. Thus, Myc controls and reduces accumulation of double-strand breaks in actively transcribed genes dependent on PAF1c.Expert Commentary: This study demonstrates that Myc maintains the integrity of the genome by transferring PFA1c to RNAPII. Targeting this process in Myc-driven tumors could form the basis for a novel cancer therapy.Endres T, Solvie D, Heidelberger JB, Andrioletti V, Baluapuri A, Ade CP, et al. Ubiquitylation of MYC couples transcription elongation with double-strand break repair at active promoters. Mol Cell 2021;81:830–844.e13.Antitumor T-cell function can be suppressed by macrophages in the tumor microenvironment (TME). Dong and colleagues identified a C1q+ tumor-associated macrophage (TAM) subset in the TME of murine lung cancers. These TAMs expressed immunomodulatory ligands whose mRNAs were destabilized by methylation of N6-methyladenosine (m6A). Depletion of the methyltransferase Mettl14 in TAMs suppressed m6A methylation and impaired T-cell differentiation, decreasing effector T cells and promoting dysfunctional CD8+ T cells in the TME. TAMs accumulated mRNA encoding Epstein-Barr virus–induced protein 3 (Ebi3), a subunit of T-cell exhaustion cytokines. Antibody-mediated neutralization of Ebi3 restored both CD8+ T-cell function and reversed immunosuppression in Mettl14-deleted mouse models. In the TME of human colon cancer patients, lower m6A-containing TAMs exhibited lower effector and higher exhausted T-cell signatures. Thus, epitranscriptomic regulation within subsets of TAMs modulates their ability to shape the TME and direct T-cell responses.Expert Commentary: The study describes contributions of transcriptional control to the immunosuppressive capacity of TAMs and reveals the promise and challenge of selectively targeting these mechanisms.Dong L, Chen C, Zhang Y, Guo P, Wang Z, Li J, et al. The loss of RNA N6-adenosine methyltransferase Mettl14 in tumor-associated macrophages promotes CD8+ T cell dysfunction and tumor growth. Cancer Cell; Published online May 20, 2021; DOI: 10.1016/j.ccell.2021.04.016.Although they have lost their transmembrane domain, oncogenic cytoplasmic receptor tyrosine kinase (RTK) fusion proteins can still activate RAS signaling. Tupule and colleagues showed that two such oncoproteins, EML4-ALK and CCDC6-RET, enrich in cytoplasmic, membrane-less biomolecular condensates. In both cases, domains in the fusion partner protein outside the kinase domain played an important role in granule formation. These oncoproteins in turn recruited a number of the adaptor and effector proteins required to activate RAS signaling. Interestingly, these signaling granules functioned by activating a pool of cytoplasmic RAS, whose function had previously been unclear. The granule-localized oncoproteins were also able to activate a subset of other signaling modules previously associated with plasma membrane-enriched RTKs. Further, forced clustering of the intracellular domain of EGFR formed cytoplasmic granules, recruited GRB2, and activated RAS signaling, suggesting that clustering in such granules is sufficient to activate cytoplasmic RAS.Expert Commentary: This work establishes a requirement for cytoplasmic biomolecular condensates in RTK oncogenic signaling, the formation and maintenance of which could be exploited to develop novel anticancer therapeutics.Tulpule A, Guan J, Neel DS, Allegakoen HR, Lin YP, Brown D, et al. Kinase-mediated RAS signaling via membraneless cytoplasmic protein granules. Cell 2021;184:2649–2664.e18.Cancer immunotherapies hinge upon reinvigorating progenitor CD8+ T effector cells. Guo and colleagues used the pleiotropic cytokine IL10 to expand and restore activity in terminally differentiated antitumor CD8+ T cells (TCF1−PD1+TIM3+). Treatment with IL10-Fc, a recombinant half-life extended fusion protein of IL10 and immunoglobulin Fc, improved control of multiple transplantable tumor models in mice, especially when combined with tumor-specific CD8+ T-cell adoptive transfer or checkpoint immunotherapies. IL10-Fc expansion of terminally exhausted CD8+ T cells was linked to specific induction of the IL10 receptor. IL10 stimulation promoted an increase in oxidative phosphorylation (OXPHOS) that was dependent upon glucose uptake and transport of pyruvate into mitochondria. OXPHOS increased the cytolytic activity of T cells and was required for the efficacy of IL10-Fc treatment. Importantly, unlike other cytokine-based immunotherapies, IL10-Fc did not generate toxic side effects.Expert Commentary: Therapeutic delivery of a half-life extended recombinant IL10 selectively expands terminally exhausted antitumor CD8+ T cells by activating OXPHOS.Guo Y, Xie YQ, Gao M, Zhao Y, Franco F, Wenes M, et al. Metabolic reprogramming of terminally exhausted CD8+ T cells by IL-10 enhances anti-tumor immunity. Nat Immunol 2021;22:746–56.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.