Hinrichs, C. | Search bioRxiv

bioRxiv2024

Immune Checkpoint Blockade Delays Cancer and Extends Survival in Murine DNA Polymerase Mutator Syndromes

Mutations in polymerases Pold1 and Pole exonuclease domains in humans are associated with increased cancer incidence, elevated tumor mutation burden (TMB) and response to immune checkpoint blockade (ICB). Although ICB is approved for treatment of several cancers, not all tumors with elevated TMB respond. Here we generated Pold1 and Pole proofreading mutator mice and show that ICB treatment of mice with high TMB tumors did not improve survival as only a subset of tumors responded. Similarly, introducing the mutator alleles into mice with Kras/p53 lung cancer did not improve survival, however, passaging mutator tumor cells in vitro without immune editing caused rejection in immune-competent hosts, demonstrating the efficiency by which cells with antigenic mutations are eliminated. Finally, ICB treatment of mutator mice earlier, before observable tumors delayed cancer onset, improved survival, and selected for tumors without aneuploidy, suggesting the use of ICB in individuals at high risk for cancer prevention. HighlightsO_LIGermline somatic and conditional Pold1 and Pole exonuclease domain mutations in mice produce a mutator phenotype. C_LIO_LISpontaneous cancers arise in mutator mice that have genomic features comparable to human tumors with these mutations. C_LIO_LIICB treatment of mutator mice with tumors did not improve survival as only a subset of tumors respond. C_LIO_LIIntroduction of the mutator alleles into an autochthonous mouse lung cancer model also did not produce immunogenic tumors, whereas passaging mutator tumor cells in vitro caused immune rejection indicating efficient selection against antigenic mutations in vivo. C_LIO_LIProphylactic ICB treatment delayed cancer onset, improved survival, and selected for tumors with no aneuploidy. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/597960v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@6cd159org.highwire.dtl.DTLVardef@243fd1org.highwire.dtl.DTLVardef@1d9da6borg.highwire.dtl.DTLVardef@192be51_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Concordant dynamic changes of global network properties in the frontoparietal and limbic compartments: an EEG study

IntroductionDespite its complexity, deciphering nodal interaction is imperative to understanding a neural network. Network interaction is an even more complicated topic that must be addressed. This study aimed to examine the relationship between the brain waves of two canonical brain structures, i.e., the frontoparietal and limbic compartments, during a resting state. MethodsElectroencephalography (EEG) of 51 subjects in eye-closed condition was analyzed, and the eLORETA method was applied to convert the signals from the scalp to the brain. By way of community detection, representative neural nodes and the associated mean activities were retrieved. Total and lagged coherences were computed to indicate functional connectivity between those neural nodes. Two global network properties were elucidated based on the connectivity measures, i.e., global efficiency and mean functional connectivity strength. The temporal correlation of the global network indices between the two studied networks was explored. ResultsIt was found that there was a significant trend of positive correlation across the four metrics (lagged vs. total coherence x global efficiency vs. average connectivity). In other words, when the neural interaction in the FP network was stronger, so did that in the limbic network, and vice versa. Notably, the above interaction was not spectrally specific and only existed at a finer temporal scale (under hundreds of milliseconds level). ConclusionThe concordant change in network properties indicates an intricate balance between FP and LM compartments. Possible mechanisms and implications for the findings are discussed.

neuroscience↗