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Achieving depletion of regulatory T cells while sparing tumor-specific effector T cells has long remained an elusive goal of immunotherapy. A new study describing the development of an antibody to the cytokine receptor CD25 optimized to ensure depletion of regulatory T cells without blocking binding of the cytokine IL-2 will reinvigorate interest in this therapeutic avenue.
The response to immunotherapy has been linked to human leukocyte antigen (HLA) genotype in certain cancers. A new study examining the interaction between cancer type–specific mutational exposures and the B44 and B27 HLA supertypes finds that patients with mutant peptides complementary to these supertypes receive the most benefit from immune-checkpoint blockade.
Immunostimulatory agents such as Toll-like receptor (TLR) agonists have shown promising antitumor efficacy but are associated with therapy-related toxicities when delivered systemically. Immune-stimulating antibody conjugates are now shown to deliver TLR agonists with potent preclinical antitumor activities.
Edelman Saul and colleagues review the challenges and strategies for implementing low-dose computed tomography screening for lung cancer in low- and middle-income countries.
Invariant natural killer T cells (iNKT cells) are innate-like CD1d-restricted T cells that have NK cell–like properties and bear an invariant T cell receptor (iTCR). iNKT cells have shown potential for cancer immunotherapy. A study now shows that stabilization of the iTCR–CD1d complex via a single-chain bi-specific antibody stimulates iNKT cell–mediated anti-tumor immunity.
Although RET alterations are relatively frequent across tumor types, specific targeting of RET in the clinic has been challenging. Ambrogio, Aggarwal and colleagues provide their views on how mechanistic studies have swiftly translated into powerful targeted therapies in two recent clinical studies that led to the FDA approval of selpercatinib for certain tumors in which RET is altered.
Beltran and colleagues discuss the challenges in treating metastatic prostate cancer and strategies to accelerate precision oncology and improve therapy and clinical decisions in this setting.
Tumor-specific changes in DNA methylation are both acquired actively through transcription-coupled processes and passively accumulated over time. Analysis across B cell malignancies now shows that these changes provide insight into the cellular origin as well as the proliferative history of tumors and thereby have diagnostic value and prognostic value, respectively.
Mitochondrial DNA damage, metabolic disruption and aging have all been associated with cancer. These three threads are now woven together to show that aging-associated somatic mutations to mitochondrial DNA alter mitochondrial serine metabolism to support cell transformation and colon-cancer development.
Effective methods for treating retinoblastoma while preserving vision are an unmet clinical need. Subretinal delivery of a hydrogel containing T cells that secrete the cytokine IL-15 and express a chimeric antigen receptor directed at the ganglioside protein GD2 completely controls retinoblastoma in immunocompromised mice, with no obvious damage to the surrounding retina.
Cancer has found a formidable foil in COVID-19, and this has brought to the fore the early concerns that COVID-19 could have a deeper impact on oncology patients. Two studies now provide insights into the enigma surrounding the determinants of the worsening of COVID-19 symptoms in patients with cancer.
Zitvogel and colleagues discuss the interplay between cancer and COVID-19 with respect to patient risk and prognosis, immune responses and potential therapies.
Immunotherapy has changed the treatment paradigm for patients with cancer, but patient selection, response assessment and treatment duration require further refinement. A recent study reports that the kinetics of circulating tumor DNA reflect response and resistance to immunotherapy treatment across multiple cancer types and could be used to tailor treatment.
Zhang and Meyerson review exciting advances in methodologies, models and datasets to study noncoding alterations in cancer, new insights into their roles in disease and potential translational implications.
The urea cycle enzyme argininosuccinate synthase 1 (ASS1) is upregulated in some cancer types. A study now shows that tumor cells with elevated urea cycle activity due to high ASS1 expression enhance gluconeogenesis, enabling a metabolic shift toward serine synthesis and causing purine synthesis addiction for growth and proliferation.
Replication stress fuels chromosomal instability, tumor heterogeneity and therapy resistance. The Sonic hedgehog pathway is now linked to an unorthodox form of replication stress in cerebellar granular-cell progenitors through deregulated firing of DNA replication origins, with implications for the pathogenesis, genomic instability and treatment of medulloblastoma.
Locally injected lipid nanoparticles that deliver RNA to elicit danger signals and simultaneously contain RNA that encodes a membrane-anchored version of the cytokine IL-12 can induce immunogenic cell death in tumors. This multipronged platform induces anticancer immune responses to the injected lesion as well as to distant tumors and hence produces an abscopal effect.
Molecular characterization of tumors informs clinical cancer care. Here, Taylor and colleagues review the progress, opportunities, and challenges of scientific and translational discovery that leverages prospective data from clinical genomic screening.
Deep learning can be used to predict genomic alterations on the basis of morphological features learned from digital histopathology. Two independent pan-cancer studies now show that automated learning from digital pathology slides and genomics can potentially delineate broader classes of molecular signatures and prognostic associations across cancer types.
