TIM-3 blockade in diffuse intrinsic pontine glioma models promotes tumor regression and antitumor immune memory.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive brain stem tumor and the leading cause of pediatric cancer-related death. To date, these tumors remain incurable, underscoring the need for efficacious therapies. In this study, we demonstrate that the immune checkpoint TIM-3 (HAVCR2) is highly expressed in both tumor cells and microenvironmental cells, mainly microglia and macrophages, in DIPG. We show that inhibition of TIM-3 in syngeneic models of DIPG prolongs survival and produces long-term survivors free of disease that harbor immune memory. This antitumor effect is driven by the direct effect of TIM-3 inhibition in tumor cells, the coordinated action of several immune cell populations, and the secretion of chemokines/cytokines that create a proinflammatory tumor microenvironment favoring a potent antitumor immune response. This work uncovers TIM-3 as a bona fide target in DIPG and supports its clinical translation.

Neuronal-Activity Dependent Mechanisms of Small Cell Lung Cancer Progression.

Neural activity is increasingly recognized as a critical regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses, while perisynaptic neurotransmitter signaling drives breast cancer brain metastasis growth. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to brain, is largely unexplored. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that, similar to glioma, metastatic SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Optogenetic stimulation of cortical neuronal activity drives proliferation and invasion of SCLC brain metastases. In the brain, SCLC cells exhibit electrical currents and consequent calcium transients in response to neuronal activity, and direct SCLC cell membrane depolarization is sufficient to promote the growth of SCLC tumors. In the lung, vagus nerve transection markedly inhibits primary lung tumor formation, progression and metastasis, highlighting a critical role for innervation in overall SCLC initiation and progression. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both primary and metastatic sites.

The landscape of tumor cell states and spatial organization in H3-K27M mutant diffuse midline glioma across age and location.

Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.