Volume 4 Issue 9, September 2023

Charles Rudin completed his MD, PhD, medical and oncology training at the University of Chicago, where he joined the department of medicine faculty in 1998. He directed the lung, esophageal and head and neck cancer program at Johns Hopkins University from 2003 to 2013, while also serving as associate cancer center director for clinical research. He joined Memorial Sloan Kettering Cancer Center in 2013 as chief of thoracic oncology, co-director of the Druckenmiller Center for Lung Cancer Research, and the Sylvia Hassenfeld Chair in Lung Cancer Research.

CD8⁺ T cells recognize tumor-associated antigens presented by major histocompatibility complex (MHC) class I molecules. How CD8⁺ T cells eliminate cancer cells deficient in MHC class I has been unclear. A study now shows that adaptive CD8⁺ T cell activation induces expression of the innate receptor NKG2D for the elimination of MHC class I–deficient tumors.

Glioblastoma is an aggressive brain tumor with a highly immunosuppressive environment that responds poorly to immune checkpoint inhibitors. A study shows that SIGLEC9⁺ monocyte-derived macrophages are enriched in glioblastomas that do not respond to immune checkpoint inhibitors, and targeting this receptor synergizes with immunotherapy.

We sought to develop a pharmacologically advanced inhibitor of the oncoprotein RET. Vepafestinib potently inhibited on-target mutants that confer resistance to approved RET inhibitors while exerting superior efficacy against intracranial disease due to enhanced penetration and retention in the brain.

This study reveals the previously underappreciated roles of CD25 (IL-2 receptor subunit-α) in IL-2 biology and cancer immunotherapy and provides mechanistic insights into the rational design of more-effective IL-2-based therapeutic agents for cancer treatment.

Treatment with immune checkpoint inhibitors (ICIs) has improved the survival of patients with metastatic melanoma. However, although ICIs are promising for achieving lasting clinical responses, only a subset of patients receive substantial benefit. Our results suggest that the IL-17 pathway supports the response of melanoma to dual ICI therapy and might represent a biomarker for patient stratification.

Resected pancreatic cancer treated pre-operatively with chemotherapy is enriched for cells that co-express GATA6, KRT17 and CYP3A. Persistent expression of GATA6^hi and KRT17^hi is associated with poor survival after treatment with mFOLFIRINOX, but not gemcitabine. CYP3A-expressing drug detoxification pathways metabolize the prodrug irinotecan, a constituent of mFOLFIRINOX, leading to persistent drug tolerance.

Jaffray and co-authors discuss progress in radiotherapy that has been driven by technological advances and ways to enable broad access to innovative radiation-based treatment modalities by aligning individualized therapy with global access needs.

In this Review, Konstantinopoulos and Matulonis discuss recent clinical advances in the treatment of ovarian cancer and reflect on persisting challenges.

Fecci and colleagues show that tumor cells having lost MHC-I, a major mechanism of immune escape, are amenable to killing by CD8⁺ T cells through an MHC-I-independent, alternative pathway via NKG2D and NKG2DL interaction and granzyme.

Jia and colleagues profile human glioblastoma samples and identify a population of macrophages characterized by Siglec-9 that drives immune evasion and immunotherapy resistance via restriction of T-cell priming. Their therapeutic elimination synergizes with immunotherapy.

Roesch and colleagues use clinical datasets and mouse models of BRAF-mutant melanoma to reveal a role for IL-17A in positive responses to anti-PD-1 and anti-CTLA-4 therapy, which they also link to infiltrating neutrophils.

Wu et al. show that versions of IL-2 that preserve CD25 activity expand tumor-specific T cells more effectively than CD25-sparing agonists and find that the efficacy of anti-PD-1 depends on the activation of PD-1⁺CD25⁺ T cells through autocrine IL-2 signaling.

Cox and colleagues develop PXS-5505, a first-in-class selective pan-lysyl oxidase inhibitor and show that it reduces chemotherapy-induced desmoplasia and stiffness, thereby improving chemotherapy response and survival in pancreatic cancer models.

Miyazaki et al. characterize vepafestinib, a next-generation RET inhibitor that is selective for wild-type RET and solvent front mutants. Due to a unique binding mode, it has enhanced brain penetrance and overcomes resistance to other RET inhibitors.

Zhou et al. investigate the molecular events that follow neoadjuvant treatment in PDAC patients, explore signatures of heterogeneous response and persister phenotypes, identify a CYP3A link to resistance and suggest that it is useful in predicting response.

Chen and colleagues, using a large multicenter prospective study, show the feasibility and survival benefits of annual screening for hepatocellular carcinoma in individuals at high risk based on hepatitis B surface antigen seropositivity.