Tumor resident, TRA anti-viral CDR3 chemical sequence motifs are associated with a better breast cancer outcome.

While for certain cancers, such as cervical cancer, the link to viral infections is very strong and very clear, other cancers represent a history of links to viral infections that are either co-morbidities or drive the cancer in ways that are not yet fully understood, for example the "hit and run" possibility. To further understand the connection of viral infections and the progress of breast cancer, we identified the chemical features of known anti-viral, T-cell receptor alpha chain (TRA) complementarity determining region-3 (CDR3) amino acid sequences among the CDR3s of breast cancer patient TRA recombinations and assessed the association of those features with patient outcomes. The application of this novel paradigm indicated consistent associations of tumor-derived, anti-CMV CDR3 chemical sequence motifs with better breast cancer patient outcomes but did not indicate an opportunity to establish risk stratifications for other cancer types. Interestingly, breast cancer samples with no detectable TRA recombinations represented a better outcome than samples with the non-anti-CMV CDR3s, further adding to a rapidly developing series of results allowing a distinction between positive and possibly harmful cancer immune responses.

Experience-Dependent Coding of Time-Dependent Frequency Trajectories by Off Responses in Secondary Auditory Cortex.

Time-dependent frequency trajectories are an inherent feature of many behaviorally relevant sounds, such as species-specific vocalizations. Dynamic frequency trajectories, even in short sounds, often convey meaningful information, which may be used to differentiate sound categories. However, it is not clear what and where neural responses in the auditory cortical pathway are critical for conveying information about behaviorally relevant frequency trajectories, and how these responses change with experience. Here, we uncover tuning to subtle variations in frequency trajectories in auditory cortex of female mice. We found that auditory cortical responses could be modulated by variations in a pure tone trajectory as small as 1/24th of an octave, comparable to what has been reported in primates. In particular, late spiking after the end of a sound stimulus was more often sensitive to the sound's subtle frequency variation compared with spiking during the sound. Such "Off" responses in the adult A2, but not those in core auditory cortex, were plastic in a way that may enhance the representation of a newly acquired, behaviorally relevant sound category. We illustrate this with the maternal mouse paradigm for natural vocalization learning. By using an ethologically inspired paradigm to drive auditory responses in higher-order neurons, our results demonstrate that mouse auditory cortex can track fine frequency changes, which allows A2 Off responses in particular to better respond to pitch trajectories that distinguish behaviorally relevant, natural sound categories.SIGNIFICANCE STATEMENT A whistle's pitch conveys meaning to its listener, as when dogs learn that distinct pitch trajectories whistled by their owner differentiate specific commands. Many species use pitch trajectories in their own vocalizations to distinguish sound categories, such as in human languages, such as Mandarin. How and where auditory neural activity encodes these pitch trajectories as their meaning is learned but not well understood, especially for short-duration sounds. We studied this in mice, where infants use ultrasonic whistles to communicate to adults. We found that late neural firing after a sound ends can be tuned to how the pitch changes in time, and that this response in a secondary auditory cortical field changes with experience to acquire a pitch change's meaning.

Becoming a better parent: Mice learn sounds that improve a stereotyped maternal behavior.

While mothering is often instinctive and stereotyped in species-specific ways, evolution can favor genetically "open" behavior programs that allow experience to shape infant care. Among experience-dependent maternal behavioral mechanisms, sensory learning about infants has been hard to separate from motivational changes arising from sensitization with infants. We developed a paradigm in which sensory learning of an infant-associated cue improves a stereotypical maternal behavior in female mice. Mice instinctively employed a spatial memory-based strategy when engaged repetitively in a pup search and retrieval task. However, by playing a sound from a T-maze arm to signal where a pup will be delivered for retrieval, mice learned within 7 days and retained for at least 2 weeks the ability to use this specific cue to guide a more efficient search strategy. The motivation to retrieve pups also increased with learning on average, but their correlation did not explain performance at the trial level. Bilaterally silencing auditory cortical activity significantly impaired the utilization of new strategy without changing the motivation to retrieve pups. Finally, motherhood as compared to infant-care experience alone accelerated how quickly the new sensory-based strategy was acquired, suggesting a role for the maternal hormonal state. By rigorously establishing that newly formed sensory associations can improve the performance of a natural maternal behavior, this work facilitates future studies into the neurochemical and circuit mechanisms that mediate novel sensory learning in the maternal context, as well as more learning-based mechanisms of parental behavior in rodents.

Blood-based T cell receptor anti-viral CDR3s are associated with worse overall survival for neuroblastoma.

With the advent of large collections of adaptive immune receptor recombination reads representing cancer, there is the opportunity to further investigate the adaptive immune response to viruses in the cancer setting. This is a particularly important goal due to longstanding but still not well-resolved questions about viral etiologies in cancer and viral infections as comorbidities. In this report, we assessed the T cell receptor complementarity determining region-3 (CDR3) amino acid (AA) sequences, for blood-sourced TCRs from neuroblastoma (NBL) cases, for exact AA sequence matches to previously identified anti-viral TCR CDR3 AA sequences. Results indicated the presence of anti-viral TCR CDR3 AA sequences in the NBL blood samples highly significantly correlated with worse overall survival. Furthermore, the TCR CDR3 AA sequences demonstrating chemical complementarity to many cytomegalovirus antigens represented cases with a worse outcome, including cases where such CDR3s were obtained from tumor samples. Overall, these results indicate a significant need for, and provide a novel strategy for assessing viral infection complications in NBL patients.

Electrostatic Complementarities of Glioblastoma-Resident T-Cell Receptors and Cancer Testis Antigens Linked to Poor Outcomes and High Levels of Sphingosine Kinase-2 Expression.

INTRODUCTION: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults. Despite a growing understanding of glioblastoma pathology, the prognosis remains poor. METHODS: In this study, we used a previously extensively benchmarked algorithm to retrieve immune receptor (IR) recombination reads from GBM exome files available from the cancer genome atlas. The T-cell receptor complementarity determining region-3 (CDR3) amino acid sequences that represent the IR recombination reads were assessed and used for the generation of chemical complementarity scores (CSs) that represent potential binding interactions with cancer testis antigens (CTAs), which is an approach particularly suited to a big data setting. RESULTS: The electrostatic CSs representing the TRA and TRB CDR3s and the CTAs, SPAG9, GAGE12E, and GAGE12F, indicated that an increased electrostatic CS was associated with worse disease-free survival (DFS). We also assessed the RNA expression of immune marker genes, which indicated that a high-level expression of SPHK2 and CIITA genes also correlated with high CSs and worse DFS. Furthermore, apoptosis-related gene expression was revealed to be lower when the TCR CDR3-CTA electrostatic CSs were high. CONCLUSION: Adaptive IR recombination reads from exome files have the potential to aid in GBM prognoses and may provide opportunities to detect unproductive immune responses.

Tumor Resident, B-Cell Receptor Chemical Characteristics Associated with Better Overall Survival for Neuroblastoma.

Pediatric neuroblastoma (NBL) is one of the most common pediatric cancers, and it can often be aggressive. Genetic and demographic factors can correlate with the severity of NBL, but the variations in the B-cell receptors (BCRs) or immunoglobulin proteins present in the NBL tumors, and their relationships to survival, are not well understood. BCRs contain variations in their complementary determining region-3 (CDR3s) amino acid sequences, due to variable recombinations of the V- and J-gene segments. Accordingly, these variations in CDR3s may represent different antigen interactions and thereby different survival probabilities. Thus, we mined the TARGET project, NBL tumor RNAseq files for BCR recombination reads. Evaluations of the physicochemical properties of IGK, IGL, and IGH CDR3s from these tumors pointed to properties of IGK and IGL in particular as associated with survival distinctions, based on several independent bioinformatics approaches, including a novel homology grouping approach facilitated by a recently developed web tool, adaptivematch.com. In conclusion, tumor resident BCR chemical features are likely useful for better risk stratification and for guiding therapy, and the availability of a user-friendly web tool will likely facilitate using BCR chemical features to meet those goals.