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Synaptic inputs from different brain areas are often targeted to distinct regions of neuronal dendritic arbors. Inputs to proximal dendrites usually produce large somatic EPSPs that efficiently trigger action potential (AP) output, whereas inputs to distal dendrites are greatly attenuated and may largely modulate AP output. In contrast to most other cortical and hippocampal neurons, hippocampal CA2 pyramidal neurons show unusually strong excitation by their distal dendritic inputs from entorhinal cortex (EC). In this study, we demonstrate that the ability of these EC inputs to drive CA2 AP output requires the firing of local dendritic Na+ spikes. Furthermore, we find that CA2 dendritic geometry contributes to the efficient coupling of dendritic Na+ spikes to AP output. These results provide a striking example of how dendritic spikes enable direct cortical inputs to overcome unfavorable distal synaptic locale to trigger axonal AP output and thereby enable efficient cortico-hippocampal information flow. Cells called neurons carry information—in the form of electrical signals—around the brain. These cells connect to each other in complex networks and each neuron is able to form junctions, or synapses, with many neighbors. In a neuron, small electrical signals start from synapses at the tips of branched structures called dendrites. From there, these signals travel to the cell body of the neuron to activate a larger electrical signal—called an action potential—that travels along a long tail-like extension, called the axon, to reach synapses with other neurons. In the dendrites, the small electrical signals can be amplified by rapid changes in the concentration of sodium ions, known as Na+ spikes. Although they were first recorded over 40 years ago, it is not clear how important the Na+ spikes are for triggering action potentials. In this study, Sun et al. studied a type of neuron in the hippocampus called CA2 pyramidal neurons, which are involved in social memory and aggression. Unlike most other neurons in this region, CA2 neurons are strongly activated by signals from a neighboring region of the brain called the entorhinal cortex. The experiments show that Na+ spikes are able to travel from the dendrites to the cell body of these neurons, where they are required to trigger action potentials. However, this is not the case for other neurons in the hippocampus, where the Na+ spikes are very weak by the time they reach the cell body. Sun et al. used a computational modeling technique to compare the different types of neurons in the hippocampus. The dendrites of these cells have different branching patterns and shapes, and the model suggests that this may explain the differences in how well the Na+ spikes travel to the cell body. The next major challenge is to understand the role of the Na+ spikes in social memory and other complex behaviors that are controlled by CA2 neurons.

Background The heterogeneity of the breast tumor microenvironment (TME) may contribute to the lack of durable responses to immune checkpoint blockade (ICB); however, mouse models to test this are currently lacking. Proper selection and use of preclinical models are necessary for rigorous, preclinical studies to rapidly move laboratory findings into the clinic. Methods Three versions of a common syngeneic model derived from the MMTV-PyMT autochthonous model were generated by inoculating 1E6, 1E5, or 1E4 cells derived from the MMTV-PyMT mouse into wildtype recipient mice. To elucidate how tumor latency and TME heterogeneity contribute to ICB resistance, comprehensive characterization of the TME using quantitative flow-cytometry and RNA expression analysis (NanoString) was performed. Subsequently, response to ICB was tested. These procedures were repeated using the EMT6 breast cancer model. Results The 3 syngeneic versions of the MMTV-PyMT model had vastly different TMEs that correlated to ICB response. The number of cells used to generate syngeneic tumors significantly influenced tumor latency, infiltrating leukocyte populations, and response to ICB. These results were confirmed using the EMT6 breast cancer model. Compared to the MMTV-PyMT autochthonous model, all 3 MMTV-PyMT syngeneic models had significantly more tumor-infiltrating lymphocytes (TILs; CD3 + , CD4 + , and CD8 + ) and higher proportions of PD-L1-positive myeloid cells, whereas the MMTV-PyMT autochthonous model had the highest frequency of myeloid cells out of total leukocytes. Increased TILs correlated with response to anti-PD-L1 and anti-CTLA-4 therapy, but PD-L1expression on tumor cells or PD-1 expression of T cells did not. Conclusions These studies reveal that tumor cell number correlates with tumor latency, TME, and response to ICB. ICB-sensitive and resistant syngeneic breast cancer models were identified, in which the 1E4 syngeneic model was most resistant to ICB. Given the lack of benefit from ICB in breast cancer, identifying robust murine models presented here provides the opportunity to further interrogate the TME for breast cancer treatment and provide novel insights into therapeutic combinations to overcome ICB resistance.

A selective class IIa histone deacetylase inhibitor induces anti-tumour immunity in a mouse model of mammary cancer through altered differentiation and recruitment of tumour-associated macrophages. Using anti-tumour macrophages in breast cancer Tumour-associated macrophages often benefit tumours, but previous efforts to either deplete or stimulate them have had some anti-tumour effects. Anthony Letai and colleagues suggest that using drugs to modify their phenotype could be even more successful. They show that a class IIa histone deacetylase inhibitor, TMP195, induces anti-tumour immunity in a mouse model of breast cancer. Treatment is associated with altered differentiation and recruitment of tumour-associated macrophages, and acts synergistically with chemotherapy and T-cell checkpoint blockade. Although the main focus of immuno-oncology has been manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumour reduction and elimination. Tumour-associated macrophages often have net pro-tumour effects 1 , but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumours. Strategies that deplete (anti-CSF-1 antibodies and CSF-1R inhibition) 2 , 3 or stimulate (agonistic anti-CD40 or inhibitory anti-CD47 antibodies) 4 , 5 tumour-associated macrophages have had some success. We hypothesized that pharmacologic modulation of macrophage phenotype could produce an anti-tumour effect. We previously reported that a first-in-class selective class IIa histone deacetylase (HDAC) inhibitor, TMP195, influenced human monocyte responses to the colony-stimulating factors CSF-1 and CSF-2 in vitro 6 . Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumour microenvironment and reduces tumour burden and pulmonary metastases by modulating macrophage phenotypes. TMP195 induces the recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumours. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumour reduction. These data introduce class IIa HDAC inhibition as a means to harness the anti-tumour potential of macrophages to enhance cancer therapy.

Although the main focus of immuno-oncology has been on manipulating the adaptive immune system, harnessing both the innate and adaptive arms of the immune system might produce superior tumor reduction and elimination. Tumor-associated macrophages (TAMs) often have net pro-tumor effects1, but their embedded location and their untapped potential provide impetus to discover strategies to turn them against tumors. Strategies that deplete (αCSF-1, CSF-1R inhibition)2,3 or stimulate (agonistic αCD40, inhibitory αCD47)4,5 TAMs have met with some success. We instead hypothesized that pharmacologic modulation of macrophage phenotype might have anti-tumor effect. We recently reported that a first-in-class selective class IIa HDAC inhibitor (TMP195) influenced human monocyte responses to colony stimulating factors CSF-1 and CSF-2 in vitro6. Here, we utilize a macrophage-dependent autochthonous mouse model of breast cancer to demonstrate that in vivo TMP195 treatment alters the tumor microenvironment and reduces tumor burden and pulmonary metastases through macrophage modulation. TMP195 induces recruitment and differentiation of highly phagocytic and stimulatory macrophages within tumors. Furthermore, combining TMP195 with chemotherapy regimens or T-cell checkpoint blockade in this model significantly enhances the durability of tumor reduction. These data introduce class IIa HDAC inhibition as a novel means to harness the anti-tumor potential of macrophages to enhance cancer therapy.