Detection of Murine Post-Pneumonectomy Lung Regeneration by 18FDG PET Imaging

Background: An intriguing biologic process in most adult mammals is post-pneumonectomy lung regeneration, that is, the removal of one lung (pneumonectomy) results in the rapid compensatory growth of the remaining lung. The spatial dependence and metabolic activity of the rodent lung during compensatory lung regeneration is largely unknown. Methods: To determine if murine lung regeneration could be detected in vivo, we studied inbred mice 3, 7, 14, and 21 days after left pneumonectomy. The remaining lung was imaged using microCT as well as the glucose tracer 2-deoxy-2-[18 F]fluoro-d-glucose (18FDG) and positron-emission tomography (PET). Because of the compliance of the murine chest wall, reproducible imaging required orotracheal intubation and pressure-controlled ventilation during scanning. Results: After left pneumonectomy, the right lung progressively enlarged over the first 3 weeks. The cardiac lobe demonstrated the greatest percentage increase in size. Dry weights of the individual lobes largely mirrored the increase in lung volume. PET/CT imaging was used to identify enhanced metabolic activity within the individual lobes. In the cardiac lobe, 18FDG uptake was significantly increased in the day 14 cardiac lobe relative to preoperative values (p < .05). In contrast, the 18FDG uptake in the other three lobes was not statistically significant at any time point. Conclusions: We conclude that the cardiac lobe is the dominant contributor to compensatory growth after murine pneumonectomy. Further, PET/CT scanning can detect both the volumetric increase and the metabolic changes associated with the regenerative growth in the murine cardiac lobe

Immune metabolism in PD-1 blockade-based cancer immunotherapy

Energy metabolism plays an important role in proliferating cells. Recent reports indicate that metabolic regulation or metabolic products can control immune cell differentiation, fate and reactions. Cancer immunotherapy based on blockade of programmed cell death protein 1 (PD-1) has been used worldwide, but a significant fraction of patients remain unresponsive. Therefore, clarifying the mechanisms and overcoming the unresponsiveness are urgent issues. Because cancer immunity consists of interactions between the cancer and host immune cells, there has recently been a focus on the metabolic interactions and/or competition between the tumor and the immune system to address these issues. Cancer cells render their microenvironment immunosuppressive, driving T-cell dysfunction or exhaustion, which is advantageous for cancer cell survival. However, accumulating mechanistic evidence of T-cell and cancer cell metabolism has gradually revealed that controlling the metabolic pathways of either type of cell can overcome T-cell dysfunction and reprogram the metabolic balance in the tumor microenvironment. Here, we summarize the role of immune metabolism in T-cell-based immune surveillance and cancer immune escape. This new concept has boosted the development of combination therapy and predictive biomarkers in cancer immunotherapy with immune checkpoint inhibitors

Current issues and perspectives in PD-1 blockade cancer immunotherapy

Programmed cell death 1 (PD-1) signal receptor blockade has revolutionized the field of cancer therapy. Despite their considerable potential for treating certain cancers, drugs targeting PD-1 still present two main drawbacks: the substantial number of unresponsive patients and/or patients showing recurrences, and side effects associated with the autoimmune response. These drawbacks highlight the need for further investigation of the mechanisms underlying the therapeutic effects, as well as the need to develop novel biomarkers to predict the lack of treatment response and to monitor potential adverse events. Combination therapy is a promising approach to improve the efficacy of PD-1 blockade therapy. Considering the increasing number of patients with cancer worldwide, solving the above issues is central to the field of cancer immunotherapy. In this review, we discuss these issues and clinical perspectives associated with PD-1 blockade cancer immunotherapy

Managing sport in the post-privatisation era in Zambia : an assessment of sporting behaviour and facilities provision in Kalulushi

Zambia, though famous for its copper production, has suffered a socio-economic distortion after privatisation of the Copper Mines from State-Parastatal (ZCCM) to private operation. The heaviest of this impact has been felt in municipal service delivery, particularly in towns on the Copperbelt Province, where services previously rendered by ZCCM including sport and recreation, have deteriorated both in quantity and quality. As noted by several scholars, even in places previously with the best sport facilities have either been abandoned or are in state of neglect. Though sport has been seen worldwide to generate both economic and social benefits, the biggest challenges though for policy making has been to determine the range of sports services and to establish whose responsibility it is to provide, avail and make accessible the range of services in question. Kalulushi has been no exception to this trend, a situation which prompted the undertaking of this exploratory case study research. The objective of the study was to explore strategies to improve management of sport in the post-privatisation era, through an assessment of the sporting behaviour and levels of facilities provision in the central area of Kalulushi. Based on two important theories and with heavy reliance on documented concepts, common measuring criteria and knowledge in sport, the author proceeded to execute the case study research. Supplemented by observations and digital pictures, closed and open-ended questionnaires were administered to residents and school respondents to assess the current sporting behaviours and sports needs. A similar set of questionnaires were administered to Local authorities, government authorities, private sports providers, former ZCCM employees and current major mining companies to assess the levels of facilities provision and to allow for a comparison in sports activities and facilities currently and before privatisation. The field data and major findings were analysed qualitatively and quantitatively aided by statistical software SPSS Version 17.0 from which the researcher has made conclusions. The research primarily established that, though the existence of infrastructure and its state has a theoretical influence on sporting behaviour, the observed poor state and distribution of sports infrastructure in the study area, did not completely hinder residents from engaging in sports activities, as evidenced by 72 % general sport participation and higher participation levels from residents with limited facilities. Most interesting still, the research identified a unique relationship between sporting behaviour and facilities provision, which relationship appeared to be more sensitive to quality as opposed to mere existence of sports facilities. This was evidenced by desertion or non utilization of run down facilities in preference or improvised facilities at home or in other public places, which observation not only fitted in the adopted model, but also paralleled existing literature which links increased participation and evoked sporting behaviour with improved quality of sports facilities. However the research further established and concluded that in fact this 72 % sport participation reflects a drop in participation compared to the time of ZCCM, attributing it to de-motivation factors including loss of interest and poor infrastructure of most designated sports areas. The findings further reveal that people have adapted by creating alternative means either by improvising facilities in public open spaces or squeezing into school infrastructure. The research identifies friendship and family influence as the major source of sporting behaviour complimented by the desire for physical fitness and social interaction. The research found out that people undertake diverse sporting activities, but noted high participation in open-door sporting activities with, Football, Netball, Basketball, Volleyball and Athletics being the most popular and participated in sports across all age groups, in schools and generally within the residents. Sport participation was generally more among respondents in schools than those outside school, further confirming the special influence schools have on society's sporting behaviour and presumable also because of the mandatory nature of sport in Zambian schools. Interestingly, the research further identified a sensitive gender relationship in participation, with males being more probable to participate than females. Generally therefore, the research concludes and confirms that sports activities and facilities were better managed in ZCCM period compared to the current situation, which assertion is justified from both pictures of remnant infrastructure and the testified declined in sport participation and sport diversity. And where as ZCCM administered a diverse range of sporting activities, and promoted sporting through regular sports festivals and sponsorship, the current research concludes that implementation of such approaches have been minimal or never attempted in the current regime except in schools where regular sports competition among schools are held. This has been accentuated by absence of sports policy, (reflected in low prioritization and non committal of adequate resources by both the private and public). This has made it difficult to identify and properly plan for the sports needs, or realize possibility of tapping the available private sector's (mining companies) contribution to the district recreation service provision. Though participation levels are relatively still high, the current deplorable state of infrastructure poses a limitation both in the sport diversity and sporting places. It is thus feared that if not abated, community motivation in sport will decline putting the district at a risky of breeding a physically inactive and poorly integrated society. Arising from these findings and conclusions, the author recommends an immediate formulation of a sport and recreation policy within the existing the framework of the existing District Strategic Plan, to guide the planning and implementation of sports related activities, which include; rehabilitation of all dilapidated infrastructure, community sensitisation on the importance of sport and information dissemination on available sports and facilities. The author also recommends recruitment of qualified personnel to oversee sporting activity and superintend over maintenance of facilities and to also curb the deduced vandalism of sports facilities. Finally tax incentives should be introduced to effectively tap the private companies' corporate social responsibilities and contribution to the district recreation service provision. The author recommends among others, further research in gender perceptions of sport participation among adults population and exploration in low cost designs for multi-facility sports arenas. Keywords: Sports, participation, facilities management, post-privatisation, Kalulush

IL-6–dependent spontaneous proliferation is required for the induction of colitogenic IL-17–producing CD8+ T cells

We propose a novel role for interleukin (IL) 6 in inducing rapid spontaneous proliferation (SP) of naive CD8+ T cells, which is a crucial step in the differentiation of colitogenic CD8+ T cells. Homeostasis of T cells is regulated by two distinct modes of cell proliferation: major histocompatibility complex/antigen–driven rapid SP and IL-7/IL-15–dependent slow homeostatic proliferation. Using our novel model of CD8+ T cell–dependent colitis, we found that SP of naive CD8+ T cells is essential for inducing pathogenic cytokine-producing effector T cells. The rapid SP was predominantly induced in mesenteric lymph nodes (LNs) but not in peripheral LNs under the influence of intestinal flora and IL-6. Indeed, this SP was markedly inhibited by treatment with anti–IL-6 receptor monoclonal antibody (IL-6R mAb) or antibiotic-induced flora depletion, but not by anti–IL-7R mAb and/or in IL-15–deficient conditions. Concomitantly with the inhibition of SP, anti–IL-6R mAb significantly inhibited the induction of CD8+ T cell–dependent autoimmune colitis. Notably, the transfer of naive CD8+ T cells derived from IL-17−/− mice did not induce autoimmune colitis. Thus, we conclude that IL-6 signaling is crucial for SP under lymphopenic conditions, which subsequently caused severe IL-17–producing CD8+ T cell–mediated autoimmune colitis. We suggest that anti–IL-6R mAb may become a promising strategy for the therapy of colitis

Beneficial effects on T cells by photodynamic therapy with talaporfin enhance cancer immunotherapy

Photodynamic therapy (PDT), a local cancer treatment using photosensitizers, has been reported to enhance antitumor immune responses by inducing immunogenic cell death. Although several studies have demonstrated the synergistic antitumor effects of PDT and immune checkpoint blockage (ICB), the detailed underlying mechanisms remain poorly understood. In this study, we investigated the immunological effects of PDT with talaporfin (Tal-PDT), a clinically approved photosensitizer, using bilateral tumor-bearing mouse models. Treatment with Tal-PDT on the tumor on one side of the mouse resulted in tumor growth inhibition on the untreated opposite side. This phenomenon, accompanied by tumor antigen-specific immune reactions, is indicative of an abscopal effect. When combined with anti PD-L1 Ab, synergistic antitumor effects were observed on both the laser-treated and untreated sides. Mechanistically, Tal-PDT enhanced the induction of XCR-1+ dendritic cells in the proximal draining lymph node likely through the induction of ferroptosis in tumor cells. This, in turn, led to the systemic generation of precursor-exhausted CD8+ T cells. Moreover, talaporfin was selectively incorporated into tumor cells rather than into tumor-infiltrating T cells in vivo, leading to targeted tumor killing while preserving T cells. These beneficial effects of Tal-PDT on anti-tumor immunity collectively enhance ICB cancer immunotherapy. Our study demonstrates the potential of combining Tal-PDT with ICB therapy for clinical applications

Identification of novel helper epitopes of MAGE-A4 tumour antigen: useful tool for the propagation of Th1 cells

MAGE-A4 has been considered as an attractive cancer-testis (CT) antigen for tumour immunotherapy. It has been well accepted that T-helper type 1 (Th1) cell-dominant immunity is critical for the successful induction of antitumour immunity in a tumour-bearing host. The adoptive Th1 cell therapy has been shown to be an attractive strategy for inducing tumour eradication in mouse systems. However, Th1-cell therapy using human tumour-specific Th1 cells, which were expanded from peripheral blood mononuclear cells (PBMCs) in a clinically useful protocol, has never been performed. Here, we first identified MAGE-A4-derived promiscuous helper epitope, peptide (MAGE-A4 280–299), bound to both HLA-DPB1*0501 and DRB1*1403. Using the peptide, we established a suitable protocol for the propagation of MAGE-A4-specific Th1 cells in vitro. Culture of CD4+ T cells with IFN-γ-treated PBMC-derived adherent cells in the presence of helper epitope peptide resulted in a great expansion of MAGE-A4-reactive Th cells producing IFN-γ , but not IL-4. Moreover, it was shown that ligation of MAGE-A4-reactive Th1 cells with the cognate peptide caused the production of IFN-γ and IL-2. Thus, our identified MAGE-A4 helper epitope peptide will become a good tool for the propagation of tumour-specific Th1 cells applicable to adoptive immunotherapy of human cancer

ICOS⁺CD4⁺ T cells define a high susceptibility to anti-PD-1 therapy-induced lung pathogenesis

がん免疫療法の副反応として発生する肺傷害に関わる免疫応答を解明 --PD-(L)1阻害による有害事象発生のマーカー発見-- . 京都大学プレスリリース. 2025-04-11.Managing immune-related adverse events (irAEs) caused by cancer immunotherapy is essential for developing effective and safer therapies. However, cellular mechanism(s) underlying organ toxicity during anti-PD-(L)1 therapy remain unclear. Here, we investigated the effect of chronological aging on anti-PD-(L)1 therapy-induced irAE-like lung toxicity, utilizing tumor-bearing aged mice. Anti-PD-(L)1 therapy facilitated ectopic infiltration of T and B cells, and antibody deposition in lung of aged but not young mice. Adoptive transfer of aged lung-derived CD4⁺ T cells into TCR-deficient mice revealed that both pathogenic CD4⁺ T cells and aged host environment were necessary for the irAE-inducible responses. Single-cell transcriptomics of lung-infiltrating cells in aged mice demonstrated that anti-PD-(L)1 therapy elicited ICOS⁺CD4⁺ T cell activation. Disruption of ICOS-ICOSL interaction attenuated germinal center B-cell differentiation and subsequent lung damage, which were overcome by local administration of IL-21 in the lung of anti-PD-1 therapy-treated aged mice. Therefore, ICOS⁺CD4⁺ T cells elicited under aged environment exacerbated aberrant immune responses and the subsequent lung dysfunction. Consistent with the findings from mouse model, ICOS up-regulation in CD4⁺ T cells was associated with later irAE incidence in patients with cancer. These finding will help development of useful strategies for irAE management in cancer patients, many of whom are elderly