A Sampling of Highlights from the Literature

The immune system declines with age, while the risk of cancer increases (from Rebelo-Marques et al. via Wikimedia Commons)Aging is a risk factor for cancer, yet the immune-related drivers of this correlation have not been completely characterized. Using a bone marrow transplant–lung cancer model, Park and colleagues report that aging-driven emergency myelopoiesis leads to the accumulation of IL1α-producing myeloid progenitor–like cells in the lung tumors. Blocking IL1α early during tumor initiation in this lung cancer model slows tumor growth as well as the onset of emergency myelopoiesis. Analysis of human lung tumor lesions shows an increase in IL1⍺-expressing monocyte-derived macrophages with age and poor outcome, highlighting the clinical relevance of the mouse data.Park M, …, Merad M. Science 2024 Sept 5;DOI:10.1126/science.adn0327.High Fn abundance may identify MSS CRC responsive to anti–PD-1 (from NCI Center for Cancer Research via NCI Visuals)Very few patients with microsatellite stable (MSS) colorectal cancer (CRC) respond to anti–PD-1 therapy. Wang and colleagues identify fecal and intratumoral abundance of Fusobacterium nucleatum (Fn) as a potential biomarker of response. Fn abundance positively correlates with outcomes for MSS CRC patients treated with anti–PD-1, and Fn enhances the antitumor effects of anti–PD-1 in both an orthotopic syngeneic model of MSS CRC and a xenograft model. Butyric acid derived from Fn decreases PD-1 expression on CD8+ tumor-infiltrating lymphocytes (TILs) via an HDAC3/8–TBX21 pathway. This reduces the frequency of PD-1+CD8+ TILs and increases that of effector CD8+ TILs, providing mechanistic insight for the potential biomarker.Wang X, …, Yu J. Cancer Cell 2024 Sept 19;42,1729-1746.e8.IL34 promotes tumorigenesis by polarizing foam-like TAMs to an M2-like phenotype (from Fig. 3 of Nian et al. Immunity 2024)How mutations in the tumor suppressor gene TP53 influence the tumor immune microenvironment is not well understood. Through RNA-sequencing analysis of Trp53WT and Trp53null spontaneous liver tumors and the generation and analysis of Il34–/– mice, Nian and colleagues find that secretion of IL34 by p53-inactivated cancer stem cells promotes liver tumorigenesis. The increased levels of IL34 promote foam-like tumor-associated macrophage (TAM) uptake of fatty acids via CD36, inducing M2-like polarization. These TAMs suppress T cell–mediated antitumor immunity. Blocking IL34 or CD36 reduced the growth of Trp53null liver tumors, providing potential therapeutic targets for cancers with TP53 mutations.Nian Z, …, Wei H. Immunity 2024 Sept 24;57,2344-2361.e7.Nanotubes enable mitochondrial transfer from bone marrow stromal cells to CD8+ T cells (from Fig. 2 of Baldwin et al. Cell 2024)Loss of mitochondrial fitness can drive T-cell exhaustion. To overcome this in the context of adoptive immunotherapies, Baldwin and colleagues developed a co-culture system that enables the transfer of mitochondria from bone marrow stromal cells to CD8+ T cells via nanotubes that form between the two cell types. CD8+ T cells that receive mitochondria have enhanced mitochondrial mass and metabolic fitness. In a mouse model of melanoma, mitochondrial transfer enhances antitumor immunity, with CD8+ T cells receiving mitochondria having improved cell expansion, survival, tumor penetrance, and effector capabilities. Similar enhancements are seen for human CD19-CAR T cells, highlighting the translational potential of the study.Baldwin JG, …, Gattinoni L. Cell 2024 Sept 13;DOI:10.1016/j.cell.2024.08.029.Reprogramming tumor cells to make them cDC1-like (from ARL Technical Library via Wikimedia Commons)Type 1 conventional dendritic cells (cDCs1) are needed for proper antigen presentation to induce tumor clearance. Using an adenoviral delivery system, Ascic and colleagues show it is possible to reprogram tumor cells in vivo, to make them more cDC1-like. Using this system to express the transcription factors PU.1, IRF8, and BATF3 in tumor cells makes them highly immunogenic and induces antitumoral effects in multiple mouse melanoma models, as well as in human tumor spheroids. The data demonstrate the potential of in vivo editing of tumor cells to be more cDC1-like as a promising therapeutic avenue.Ascic E, ..., Pereira CF. Science 2024 Sept 5;DOI:10.1126/science.adn9083.Fc–IL-4 reinvigorates terminally exhausted CD8+ T cells to fight cancer (from j4p4n via Openclipart)Most studies on tumor immunity focus on eliciting type 1 immune responses. However, a recent study shows the type 2 cytokine IL4 can be harnessed for cancer immunotherapy. Using an Fc–IL4 fusion protein, Feng and colleagues demonstrate enhanced antitumor activity with both immune checkpoint blockade and adoptive T-cell transfer therapies. Fc–IL4 reprograms CD8+ T cells by inducing STAT6 and mTOR signaling, accompanied with an increase in glycolytic metabolism, which reinvigorates terminally exhausted CD8+ T cells. This study adds to the growing evidence that type 2 immunity, previously thought of as protumor, can also contribute to antitumor effects under certain circumstances.Feng B, …, Tang L. Nature 2024 Sept 25;634,712–720.