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Animal experiments are often used to determine effects of drugs and other biological conditions on cancer progression, but poor accuracy and reproducibility of established tumor measurement methods make results unreliable. In orthotopic mouse models of head and neck cancer, tumor volumes approximated from caliper measurements are conventionally used to compare groups, but geometrical challenges make the procedure imprecise. To address this, we developed software to better measure these tumors by automated analysis of cone-beam computed tomography (CBCT) scans. This allows for analyses of tumor shape and growth dynamics that would otherwise be too inaccurate to provide biological insight. Monitoring tumor growth by calipers and imaging in parallel, we find that caliper measurements of small tumors are weakly correlated with actual tumor volume and highly susceptible to experimenter bias. The method presented provides a unique window to sources of error in a foundational aspect of preclinical head and neck cancer research and a valuable tool to mitigate them. [ABSTRACT FROM AUTHOR]

Between 1967 and 1973 Cornelius Cardew taught at three different London institutions—a traditional music conservatory (the Royal Academy of Music), an adult education college (Morley College), and a politically radical free school (the Antiuniversity of London). These schools introduced Cardew to a wide range of technical musical abilities and profoundly affected the composer's works and pedagogy, culminating in a new musical organization: the Scratch Orchestra. This essay details the political implications of Cardew's teaching philosophy within the Scratch Orchestra and the lessons to be gleaned from the Orchestra's successes and failures, particularly the fundamental necessity of disagreement in egalitarian musical classrooms and improvisatory collaborations. To amplify these lessons, I analyse how the musical structures of 'Paragraph 2' of Cardew's The Great Learning belie the composer's own politics by prescribing distinctly hierarchical performance roles. [ABSTRACT FROM AUTHOR]

Though their cultural births coincided, punk and rap musicians performed in New York City for at least seven years before they endeavoured any substantial creative interactions. Musicians, critics, and fans referred to both punk and rap as 'primitive'; however, this article compares the acceptance and celebration of punk as 'primitive' with inverted judgments of shared qualities in rap music. Specifically, this article considers New York punk in the 1970s as a white racial project. Persistent stereotypes in white music media, particularly rock criticism, constructed the discursive meanings of punk and rap, while institutional and political segregation structured this distinction. Artistic 'amateurism', thus, functions as a celebratory term only when we give such art the benefit of the doubt – that it is not mere ineptness, that it is fruitful, that it is intentional, or that it is subversive. This benefit, in this case, is a white privilege. [ABSTRACT FROM AUTHOR]

Typical accounts of punk locate “Year Zero” in 1976. Implying the death of an old order and the beginning of an entirely new epoch, punk discourses contain no shortage of grandiose claims about how punk permanently altered the course of not only popular music, but also the entire world. The standard historical narrative has come to resemble a mythology, with the Sex Pistols as the central figures responsible for instigating this transformation. Drawing upon the primary propagators of this narrative (Malcolm McLaren, Greil Marcus, and Jon Savage), and a contemporary portrayal of the Sex Pistols mythology in the film24 Hour Party People, this article argues that a distinct strand of messianism marks the common historical narrative of punk. Walter Benjamin and Alain Badiou provide theoretical models for how scholars might recognize the intellectual consequences of this historiography. [ABSTRACT FROM PUBLISHER]

Clinically approved head and neck squamous cell carcinoma (HNSCC) immunotherapies manipulate the immune checkpoint blockade (ICB) axis but have had limited success outside of recurrent/metastatic disease. Interleukin-7 (IL7) has been shown to be essential for effector T-cell survival, activation, and proliferation. Here, we show that IL7 in combination with radiotherapy (RT) is effective in activating CD8 + T-cells for reducing tumor growth. Our studies were conducted using both human papillomavirus related and unrelated orthotopic HNSCC murine models. Immune populations from the tumor, draining lymph nodes, and blood were compared between treatment groups and controls using flow cytometry, proteomics, immunofluorescence staining, and RNA sequencing. Treatment with RT and IL7 (RT + IL7) resulted in significant tumor growth reduction, high CD8 T-cell tumor infiltration, and increased proliferation of T-cell progenitors in the bone marrow. IL7 also expanded a memory-like subpopulation of CD8 T-cells. These results indicate that IL7 in combination with RT can serve as an effective immunotherapy strategy outside of the conventional ICB axis to drive the antitumor activity of CD8 T-cells. [ABSTRACT FROM AUTHOR]

Resistance to radiation therapy (RT) remains an obstacle in HPV-negative head and neck squamous cell carcinomas (HNSCCs)—even with a combined RT-immunotherapy approach. Jak-Stat proteins have long been studied for both their immune regulatory role in the host immune response as well as their cancer cell signaling role in shaping the tumor microenvironment (TME). Here, we identify STAT1 as a mediator of radioresistance in HPV-negative preclinical mouse models of HNSCC, by which knockout of STAT1 in the cancer cell (STAT1 KO)—but not in the host—resulted in decreased tumor growth alongside increased immune activation. We show that RT increases STAT1/pSTAT1 expression, which may act as a marker of radioresistance. Whereas RT increased JAK-STAT and interferon (IFN) signaling, transcriptomic analysis revealed that STAT1 KO in the cancer cell resulted in decreased expression of IFN-associated genes of resistance. In vitro experiments showed that STAT1 KO increased T cell chemoattraction and decreased baseline growth. These results indicate that STAT1 may serve a tumor-promoting role in the cancer cell and will inform biomarker development and treatment regimens for HNSCC incorporating RT. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) has a heterogeneous tumor microenvironment (TME) comprised of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages, neutrophils, regulatory T cells, and myofibroblasts. The precise mechanisms that regulate the composition of the TME and how they contribute to radiotherapy (RT) response remain poorly understood. In this study, we analyze changes in immune cell populations and circulating chemokines in patient samples and animal models of pancreatic cancer to characterize the immune response to radiotherapy. Further, we identify STAT3 as a key mediator of immunosuppression post-RT. We found granulocytic MDSCs (G-MDSCs) and neutrophils to be increased in response to RT in murine and human PDAC samples. We also found that RT-induced STAT3 phosphorylation correlated with increased MDSC infiltration and proliferation. Targeting STAT3 using an anti-sense oligonucleotide in combination with RT circumvented RT-induced MDSC infiltration, enhanced the proportion of effector T cells, and improved response to RT. In addition, STAT3 inhibition contributed to the remodeling of the PDAC extracellular matrix when combined with RT, resulting in decreased collagen deposition and fibrotic tissue formation. Collectively, our data provide evidence that targeting STAT3 in combination with RT can mitigate the pro-tumorigenic effects of RT and improve tumor response. [ABSTRACT FROM AUTHOR]

Background: Radioresistance represents a major problem in the treatment of head and neck cancer (HNC) patients. To improve response, understanding tumor microenvironmental factors that contribute to radiation resistance is important. Regulatory T cells (Tregs) are enriched in numerous cancers and can dampen the response to radiation by creating an immune-inhibitory microenvironment. The purpose of this study was to investigate mechanisms of Treg modulation by radiation in HNC.Methods: We utilized an orthotopic mouse model of HNC. Anti-CD25 was used for Treg depletion. Image-guided radiation was delivered to a dose of 10 Gy. Flow cytometry was used to analyze abundance and function of intratumoral immune cells. Enzyme-linked immunosorbent assay was performed to assess secreted factors. For immune-modulating therapies, anti-PD-L1, anti-CTLA-4, and STAT3 antisense oligonucleotide (ASO) were used. All statistical tests were two-sided.Results: Treatment with anti-CD25 and radiation led to tumor eradication (57.1%, n = 4 of 7 mice), enhanced T-cell cytotoxicity compared with RT alone (CD4 effector T cells [Teff]: RT group mean = 5.37 [ 0.58] vs RT + αCD25 group mean =10.71 [0.67], P = .005; CD8 Teff: RT group mean = 9.98 [0.81] vs RT + αCD25 group mean =16.88 [2.49], P = .01) and induced tumor antigen-specific memory response (100.0%, n = 4 mice). In contrast, radiation alone or when combined with anti-CTLA4 did not lead to durable tumor control (0.0%, n = 7 mice). STAT3 inhibition in combination with radiation, but not as a single agent, improved tumor growth delay, decreased Tregs, myeloid-derived suppressor cells, and M2 macrophages and enhanced effector T cells and M1 macrophages. Experiments in nude mice inhibited the benefit of STAT3 ASO and radiation.Conclusion: We propose that STAT3 inhibition is a viable and potent therapeutic target against Tregs. Our data support the design of clinical trials integrating STAT3 ASO in the standard of care for cancer patients receiving radiation. [ABSTRACT FROM AUTHOR]

In pancreatic ductal adenocarcinoma (PDAC) patients, we show that response to radiation therapy (RT) is characterized by increased IL-2Rβ and IL-2Rγ along with decreased IL-2Rα expression. The bispecific PD1-IL2v is a PD-1-targeted IL-2 variant (IL-2v) immunocytokine with engineered IL-2 cis targeted to PD-1 and abolished IL-2Rα binding, which enhances tumor-antigen-specific T cell activation while reducing regulatory T cell (Treg) suppression. Using PD1-IL2v in orthotopic PDAC KPC-driven tumor models, we show marked improvement in local and metastatic survival, along with a profound increase in tumor-infiltrating CD8+ T cell subsets with a transcriptionally and metabolically active phenotype and preferential activation of antigen-specific CD8+ T cells. In combination with single-dose RT, PD1-IL2v treatment results in a robust, durable expansion of polyfunctional CD8+ T cells, T cell stemness, tumor-specific memory immune response, natural killer (NK) cell activation, and decreased Tregs. These data show that PD1-IL2v leads to profound local and distant response in PDAC. [Display omitted] • RT + PD1-IL2v reduces tumor growth and metastasis by enhancing CD8 T cell function • RT + PD1-IL2v reduces tumoral Tregs while increasing systemic NK cell frequency • RT + PD1-IL2v induces a durable memory response, evidenced by tumor eradication • Human PDAC patients upregulate molecular targets of PD1-IL2v post-RT Piper and Hoen et al. show that a combination of radiation and PD1-IL2v immunotherapy enhances CD8+ T cell polyfunctionality, activation, and immune memory across tumor, lymph node, and blood compartments and results in a durable local and systemic anti-tumor response. [ABSTRACT FROM AUTHOR]