bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2024–12–01
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.
  2. The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.
  3. Functional subsets of tumor-specific CD8+ T cells in draining lymph nodes and tumor microenvironment.
  4. Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
  5. Human CD8+ T cell map with single-cell transcriptome and TCR information.
  6. Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.
  7. Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.
  8. Stayin' Alive: Targeting chromatin regulators of clonal hematopoiesis promotes CD8 T cell stemness.
  9. Unlocking the full potential of memory T cells in adoptive T cell therapy for hematologic malignancies.
  10. An integrated single-cell atlas of blood immune cells in aging.
  11. Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8+ T cells.
  12. STAT5 activation enhances adoptive therapy combined with peptide vaccination by preventing PD-1 inhibition.
  13. Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity.
  14. How do autoimmune CD4+ T cells handle exhaustion?
  15. TCF1 dosage determines cell fate during T cell development.
  16. Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma.
  17. Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth.
  18. Immune Alterations with Aging: Mechanisms and Intervention Strategies.
  19. The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies.
  20. Rab8a restores diverse innate functions in CD11c+CD11b+ dendritic cells from aged mice.
  1. bioRxiv. 2024 Nov 15. pii: 2024.11.14.621733. [Epub ahead of print]
    Dietary Restriction Enhances CD8⁺ T Cell Ketolysis to Limit Exhaustion and Boost Anti-Tumor Immunity.
    Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Shixin Ma, McLane J Watson, Ryan D Sheldon, Michael P Vincent, Benjamin K Johnson, Abigail E Ellis, Molly T Soper-Hopper, Christine N Isaguirre, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Connie M Krawczyk, Russell G Jones.
      Reducing calorie intake without malnutrition limits tumor progression but the underlying mechanisms are poorly understood. Here we show that dietary restriction (DR) suppresses tumor growth by enhancing CD8 + T cell-mediated anti-tumor immunity. DR reshapes CD8 + T cell differentiation within the tumor microenvironment (TME), promoting the development of effector T cell subsets while limiting the accumulation of exhausted T (Tex) cells, and synergizes with anti-PD1 immunotherapy to restrict tumor growth. Mechanistically, DR enhances CD8 + T cell metabolic fitness through increased ketone body oxidation (ketolysis), which boosts mitochondrial membrane potential and fuels tricarboxylic acid (TCA) cycle-dependent pathways essential for T cell function. T cells deficient for ketolysis exhibit reduced mitochondrial function, increased exhaustion, and fail to control tumor growth under DR conditions. Our findings reveal a critical role for the immune system in mediating the anti-tumor effects of DR, highlighting nutritional modulation of CD8 + T cell fate in the TME as a critical determinant of anti-tumor immunity.
    DOI:  https://doi.org/10.1101/2024.11.14.621733
  2. Sci Immunol. 2024 Nov 29. 9(101): eadk2954
    The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation.
    Ziang Zhu, Ying Luo, Guohua Lou, Kiddist Yihunie, Safuwra Wizzard, Andrew W DeVilbiss, Sarah Muh, Chaoyu Ma, Sejal S Shinde, Jonathan Hoar, Taidou Hu, Nu Zhang, Shyam Biswal, Ralph J DeBerardinis, Tuoqi Wu, Chen Yao.
      During persistent antigen stimulation, exhausted CD8+ T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8+ T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell-intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8+ T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8+ GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8+ T cells and long-term T cell immunity during chronic antigen exposure.
    DOI:  https://doi.org/10.1126/sciimmunol.adk2954
  3. Curr Opin Immunol. 2024 Nov 25. pii: S0952-7915(24)00096-7. [Epub ahead of print]92 102506
    Functional subsets of tumor-specific CD8+ T cells in draining lymph nodes and tumor microenvironment.
    Qizhao Huang, Lifan Xu, Lilin Ye.
      Accumulating evidence demonstrates that tumor-specific CD8+ T cells in tumor-draining lymph nodes (TdLNs) act as an upstream reservoir of exhausted subsets within tumor microenvironment (TME). This reservoir primarily consists of progenitor exhausted CD8+ T (TPEX) cells and newly defined tumor-specific memory subsets (TTSM). We propose that these two subsets work together to mediate the antitumor effects of PD-1/PD-L1 immune checkpoint blockade (ICB) in a spatiotemporal manner. Although PD-1/PD-L1 ICB monotherapy drives the proliferation and further differentiation of these subsets, it does not alter the programmed differentiation trajectory from TTSM cells to TPEX cells, ultimately leading to the development of terminally exhausted CD8+ T cells. This phenomenon may partly explaining the frequent relapse in patients following initial ICB therapy. In this review, we focus on the phenotypic and functional heterogeneity of tumor-specific CD8+ T cells in both TdLNs and the TME and discuss the implications of these studies for ICB. Our insights aim to illuminate new strategies for advancing tumor immunotherapies.
    DOI:  https://doi.org/10.1016/j.coi.2024.102506
  4. Int J Mol Sci. 2024 Nov 14. pii: 12223. [Epub ahead of print]25(22):
    Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
    Jing Wang, Yuanli He, Feiming Hu, Chenchen Hu, Yuanjie Sun, Kun Yang, Shuya Yang.
      Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.
    Keywords:  immune cells; immunotherapy; metabolic reprogramming; the tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms252212223
  5. Nat Methods. 2024 Nov 29.
    Human CD8+ T cell map with single-cell transcriptome and TCR information.
      
    DOI:  https://doi.org/10.1038/s41592-024-02529-7
  6. Nat Aging. 2024 Nov 25.
    Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.
    Brittany L Angarola, Siddhartha Sharma, Neerja Katiyar, Hyeon Gu Kang, Djamel Nehar-Belaid, SungHee Park, Rachel Gott, Giray N Eryilmaz, Mark A LaBarge, Karolina Palucka, Jeffrey H Chuang, Ron Korstanje, Duygu Ucar, Olga Anczukόw.
      Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes. Aged stromal cells downregulate fibroblast marker genes and upregulate markers of senescence and cancer-associated fibroblasts. Among immune cells, distinct T cell subsets (Gzmk+, memory CD4+, γδ) and M2-like macrophages expand with age. Spatial transcriptomics reveals co-localization of aged immune and epithelial cells in situ. Lastly, we found transcriptional signatures of aging mammary cells in human breast tumors, suggesting possible links between aging and cancer. Together, these data uncover that epithelial, immune and stromal cells shift in proportions and cell identity, potentially impacting cell plasticity, aged microenvironment and neoplasia risk.
    DOI:  https://doi.org/10.1038/s43587-024-00751-8
  7. Int Immunopharmacol. 2024 Nov 26. pii: S1567-5769(24)02224-0. [Epub ahead of print]144 113702
    Emerging role of metabolic reprogramming in the immune microenvironment and immunotherapy of thyroid cancer.
    Shouhua Li, Hengtong Han, Kaili Yang, Xiaoxiao Li, Libin Ma, Ze Yang, Yong-Xun Zhao.
      The metabolic reprogramming of cancer cells is a hallmark of many malignancies. To meet the energy acquisition needs of tumor cells for rapid proliferation, tumor cells reprogram their nutrient metabolism, which is caused by the abnormal expression of transcription factors and signaling molecules related to energy metabolic pathways as well as the upregulation and downregulation of abnormal metabolic enzymes, receptors, and mediators. Thyroid cancer (TC) is the most common endocrine tumor, and immunotherapy has become the mainstream choice for clinical benefit after the failure of surgical, endocrine, and radioiodine therapies. TC change the tumor microenvironment (TME) through nutrient competition and metabolites, causing metabolic reprogramming of immune cells, profoundly changing immune cell function, and promoting immune evasion of tumor cells. A deeper understanding of how metabolic reprogramming alters the TME and controls immune cell fate and function will help improve the effectiveness of TC immunotherapy and patient outcomes. This paper aims to elucidate the metabolic communication that occurs between immune cells around TC and discusses how metabolic reprogramming in TC affects the immune microenvironment and the effectiveness of anti-cancer immunotherapy. Finally, targeting key metabolic checkpoints during metabolic reprogramming, combined with immunotherapy, is a promising strategy.
    Keywords:  Immune microenvironment; Immunometabolism; Immunotherapy; Metabolic reprogramming; Thyroid cancers
    DOI:  https://doi.org/10.1016/j.intimp.2024.113702
  8. Cancer Res. 2024 Nov 26.
    Stayin' Alive: Targeting chromatin regulators of clonal hematopoiesis promotes CD8 T cell stemness.
    Xingjian Qiu, Aaron Yang, Amanda C Poholek.
      T cell exhaustion remains a significant barrier to immunotherapeutic success for many patients with solid tumors. Growing evidence suggests that enhanced survival and self-renewal properties of a stem-like precursor T cell population (Tpex) is correlated with a survival advantage in immunotherapy. In a recent study published in Science, Kang and colleagues find three epigenetic regulators commonly mutated in clonal hematopoiesis also control Tpex progression to exhaustion. By leveraging the finding that patients with enhanced survival in myelodysplastic syndrome (MDS) had T cell mutations in the ASXL1 gene, this study demonstrates that loss of ASXL1 in T cells preserves their stem-cell like properties of self-renewal and survival leading to increased anti-tumor responses when combined with immunotherapy in both mouse models and human cancers. These findings have significant implications for new therapeutic options that target epigenetic modifiers promoting exhaustion together with immune checkpoint blockade to improve response rates in patients.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4458
  9. Int Immunopharmacol. 2024 Nov 27. pii: S1567-5769(24)01914-3. [Epub ahead of print]144 113392
    Unlocking the full potential of memory T cells in adoptive T cell therapy for hematologic malignancies.
    Ding-Ya Sun, Yi-Jie Hu, Xin Li, Jun Peng, Zhi-Jie Dai, Shan Wang.
      In recent years, immune cell therapy, particularly adoptive cell therapy (ACT), has shown superior therapeutic effects on hematologic malignancies. However, a challenge lies in ensuring that genetically engineered specific T cells maintain lasting anti-tumor effects within the host. The enduring success of ACT therapy hinges on the persistence of memory T (TM) cells, a diverse cell subset crucial for tumor immune response and immune memory upkeep. Notably, TM cell subsets at varying differentiation stages exhibit distinct biological traits and anti-tumor capabilities. Poorly differentiated TM cells are pivotal for favorable clinical outcomes in ACT. The differentiation of TM cells is influenced by multiple factors, including metabolism and cytokines. Consequently, current research focuses on investigating the differentiation patterns of TM cells and enhancing the production of poorly differentiated TM cells with potent anti-tumor properties in vitro, which is a prominent area of interest globally. This review delves into the differentiation features of TM cells, outlining their distribution in patients and their impact on ACT treatment. It comprehensively explores cutting-edge strategies to boost ACT efficacy through TM cell differentiation induction, aiming to unlock the full potential of TM cells in treating hematologic malignancies and offering novel insights for tumor immune cell therapy.
    Keywords:  Adoptive T cell therapy; Hematologic malignancies; Memory T cell; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.intimp.2024.113392
  10. NPJ Aging. 2024 Nov 29. 10(1): 59
    An integrated single-cell atlas of blood immune cells in aging.
    Igor Filippov, Leif Schauser, Pärt Peterson.
      Recent advances in single-cell technologies have facilitated studies on age-related alterations in the immune system. However, previous studies have often employed different marker genes to annotate immune cell populations, making it challenging to compare results. In this study, we combined seven single-cell transcriptomic datasets, comprising more than a million cells from one hundred and three donors, to create a unified atlas of human peripheral blood mononuclear cells (PBMC) from both young and old individuals. Using a consistent set of marker genes for immune cell annotation, we standardized the classification of immune cells and assessed their prevalence in both age groups. The integrated dataset revealed several consistent trends related to aging, including a decline in CD8+ naive T cells and MAIT cells and an expansion of non-classical monocyte compartments. However, we observed significant variability in other cell types. Our analysis of the long non-coding RNA MALAT1hi T cell population, previously implicated in age-related T cell exhaustion, showed that this population is highly heterogeneous with a mixture of naïve-like and memory-like cells. Despite substantial variation among the datasets when comparing gene expression between age groups, we identified a high-confidence signature of CD8+ naive T cell aging marked by an increased expression of pro-inflammatory genes. In conclusion, our study emphasizes the importance of standardizing existing single-cell datasets to enable the comprehensive examination of age-related cellular changes across multiple datasets.
    DOI:  https://doi.org/10.1038/s41514-024-00185-x
  11. Clin Transl Immunology. 2024 ;13(11): e70014
    Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8+ T cells.
    Susan N Christo, Keely M McDonald, Thomas N Burn, Nadia Kurd, Jessica Stanfield, Megan M Kaneda, Ruth Seelige, Christopher P Dillon, Timothy S Fisher, Bas Baaten, Laura K Mackay.
       Objectives: Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8+ T cells has yet to be fully elucidated.
    Methods: CD8+ T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8+ T cells. Immune responses were also compared with anti-PD-L1 monotherapy to assess the advantage of dual checkpoint targeting.
    Results: We found that CD47 × PD-L1 BisAb treatment augmented CD8+ T cell responses in tumors, which resulted in enhanced tumor control. Compared with anti-PD-L1 treatment, dual CD47 and PD-L1 blockade promoted greater numbers of antigen-specific tumor-resident CD8+ T cells that exhibited increased cytokine production.
    Conclusions: Engagement of innate and adaptive immune checkpoint molecules via CD47 × PD-L1 BisAb treatment resulted in robust CD8+ T cell responses, including the induction of tumor-resident CD8+ T cells that exhibited functionally superior anti-tumor immunity. These results demonstrate that innate immune activation potentiates anti-tumor adaptive responses, highlighting the use of dual checkpoint blockade as an optimal strategy for promoting CD8+ T cell-mediated protection.
    Keywords:  CD47; CD8+ T cells; adaptive immunity; immune checkpoint blockade; immunotherapy; tumor‐resident CD8+ T cells
    DOI:  https://doi.org/10.1002/cti2.70014
  12. Mol Cancer Ther. 2024 Nov 25.
    STAT5 activation enhances adoptive therapy combined with peptide vaccination by preventing PD-1 inhibition.
    Aaron E Fan, Hussein Sultan, Takumi Kumai, Valentyna I Fesenkova, Juan Wu, John D Klement, Joshua D Bernstock, Gregory K Friedman, Esteban Celis.
      Adoptive cell therapy (ACT) using retrovirally transduced T cells represents a promising strategy for enhancing antitumor responses. When used with TriVax, a peptide vaccination strategy, this approach synergistically expands antigen-specific cell populations. STAT5 plays a vital role as a transcription factor in regulating T cell proliferation and their differentiation into effector and memory T cells. We aimed to explore the combination therapy using CD8 T cells engineered to express constitutively active STAT5 (CA-STAT5) with vaccines. CD8 T cells were transduced with a retrovirus (RV) encoding the mouse gp100 T cell receptor (TCR). In certain treatment groups, cells were also co-transduced with RV encoding CA-STAT5. We assessed transduction efficiency and functional activity through flow cytometry and various functional assays. B16F10 tumor-bearing mice were treated with ACT using RV-transduced CD8 T cells and subsequently vaccinated with TriVax. We demonstrate that TriVax selectively enhanced the expansion of ACT cell populations bearing gp100-specific TCRs. T cells engineered to express CA-STAT5 showed not only increased expansion and polyfunctionality but also reduced PD-1 expression, leading to decreased cellular exhaustion. In a B16F10 melanoma mouse model, our approach yielded a potent antitumor effect, with CA-STAT5 further amplifying this response. We found that CA-STAT5 improved antitumor activities, in part, by attenuating the PD-1/PD-L1 inhibitory pathway. These findings indicate that TCR-transduced CD8 T cells can undergo antigen-dependent expansion when exposed to TriVax. Additionally, the expression of CA-STAT5 enhances T cell proliferation and persistence, partly by promoting resistance to PD-1/PD-L1-mediated inhibition in antitumor T cells.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0505
  13. Nat Aging. 2024 Nov 26.
    Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity.
    Siyu Pei, Xiuyu Deng, Ruirui Yang, Hui Wang, Jian-Hong Shi, Xueqing Wang, Jia Huang, Yu Tian, Rongjing Wang, Sulin Zhang, Hui Hou, Jing Xu, Qingcheng Zhu, Huan Huang, Jialing Ye, Cong-Yi Wang, Wei Lu, Qingquan Luo, Zhi-Yu Ni, Mingyue Zheng, Yichuan Xiao.
      Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8+ tissue resident memory T (TRM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8+ T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8+ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated TRM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8+ T cells by restoring TRM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8+ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced TRM restriction as a key mechanism causing aged CD8+ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.
    DOI:  https://doi.org/10.1038/s43587-024-00746-5
  14. Trends Immunol. 2024 Nov 27. pii: S1471-4906(24)00275-8. [Epub ahead of print]
    How do autoimmune CD4+ T cells handle exhaustion?
    Astrid Fabri, Lucy S K Walker.
      Chronic antigen exposure is frequently associated with T cell exhaustion. In a recent study, Aljobaily et al. show that pancreatic islet-infiltrating CD4+ T cells in mouse autoimmune diabetes may circumvent exhaustion by preserving TCF1 expression. Continuous recruitment of epigenetically pre-programmed CD62L+ CD4+ T cells seems to sustain the local autoimmune response.
    Keywords:  CD4 T cell; autoimmunity; exhaustion; stemness; type 1 diabetes
    DOI:  https://doi.org/10.1016/j.it.2024.11.004
  15. Sci Adv. 2024 Nov 29. 10(48): eado5982
    TCF1 dosage determines cell fate during T cell development.
    Anjali Verma, Bridget Aylward, Fei Ma, Cheryl A Sherman, Laura Chopp, Susan Shinton, Roshni Roy, Shawn Fahl, Alejandra Contreras, Byron Koenitzer, Parirokh Awasthi, Krystyna Mazan-Mamczarz, Supriyo De, Noah Ollikainen, Xiang Qiu, Remy Bosselut, Ranjan Sen, David L Wiest, Jyoti Misra Sen.
      Loss-of-function studies have shown that transcription factor T cell factor-1 (TCF1), encoded by the Tcf7 gene, is essential for T cell development in the thymus. We discovered that the Tcf7 expression level is regulated by E box DNA binding proteins, independent of Notch, and regulates αβ and γδ T cell development. Systematic interrogation of the five E protein binding elements (EPE1-5) in the Tcf7 enhancer region showed lineage-specific utilization. Specifically, loss-of-function analysis revealed that only EPE3 plays a critical role in supporting αβ T cell development, while EPE1, 3, and 5 regulate the γδ T cell maturation and functional cell fate decision. The importance of EPE3 in supporting both lineages may stem from its unique capacity to interact with the Tcf7 transcriptional start site. Together, these studies demonstrate that the precise dosage of TCF1 expression mediated by distinct EPEs generates a balanced output of T cells from the thymus.
    DOI:  https://doi.org/10.1126/sciadv.ado5982
  16. Nat Immunol. 2024 Nov 28.
    Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma.
    Benjamin Y Lu, Liliana E Lucca, Wesley Lewis, Jiping Wang, Catarina V Nogueira, Sebastian Heer, Violeta Rayon-Estrada, Pierre-Paul Axisa, Sarah M Reeves, Nicholas C Buitrago-Pocasangre, Giang H Pham, Mina L Kojima, Wei Wei, Lilach Aizenbud, Antonietta Bacchiocchi, Lin Zhang, Joseph J Walewski, Veronica Chiang, Kelly Olino, James Clune, Ruth Halaban, Yuval Kluger, Anthony J Coyle, Jan Kisielow, Franz-Josef Obermair, Harriet M Kluger, David A Hafler.
      Effective anti-tumor immunity is driven by cytotoxic CD8+ T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8+ T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR+CD8+ regulatory T cells target other tumor-antigen-specific CD8+ T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8+ T cells and implicate KIR+CD8+ regulatory T cells as a cellular mediator of immune evasion in human cancer.
    DOI:  https://doi.org/10.1038/s41590-024-02023-4
  17. Nat Commun. 2024 Nov 28. 15(1): 10312
    Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth.
    Rasha Barakat, Jit Chatterjee, Rui Mu, Xuanhe Qi, Xingxing Gu, Igor Smirnov, Olivia Cobb, Karen Gao, Angelica Barnes, Jonathan Kipnis, David H Gutmann.
      In solid cancers, T cells typically function as cytotoxic effectors to limit tumor growth, prompting therapies that capitalize upon this antineoplastic property (immune checkpoint inhibition; ICI). Unfortunately, ICI treatments have been largely ineffective for high-grade brain tumors (gliomas; HGGs). Leveraging several single-cell RNA sequencing datasets, we report greater CD8+ exhausted T cells in human pediatric low-grade gliomas (LGGs) relative to adult and pediatric HGGs. Using several preclinical mouse LGG models (Nf1-OPG mice), we show that these PD1+/TIGIT+ CD8+ exhausted T cells are restricted to the tumor tissue, where they express paracrine factors necessary for OPG growth. Importantly, ICI treatments with α-PD1 and α-TIGIT antibodies attenuate Nf1-OPG tumor proliferation through suppression of two cytokine (Ccl4 and TGFβ)-mediated mechanisms, rather than by T cell-mediated cytotoxicity, as well as suppress monocyte-controlled T cell chemotaxis. Collectively, these findings establish a previously unrecognized function for CD8+ exhausted T cells as specialized regulators of LGG maintenance.
    DOI:  https://doi.org/10.1038/s41467-024-54569-4
  18. Nutrients. 2024 Nov 08. pii: 3830. [Epub ahead of print]16(22):
    Immune Alterations with Aging: Mechanisms and Intervention Strategies.
    Weiru Yu, Yifei Yu, Siyuan Sun, Chenxu Lu, Jianan Zhai, Yumei Lei, Feirong Bai, Ran Wang, Juan Chen.
      Aging is the result of a complex interplay of physical, environmental, and social factors, leading to an increased prevalence of chronic age-related diseases that burden health and social care systems. As the global population ages, it is crucial to understand the aged immune system, which undergoes declines in both innate and adaptive immunity. This immune decline exacerbates the aging process, creating a feedback loop that accelerates the onset of diseases, including infectious diseases, autoimmune disorders, and cancer. Intervention strategies, including dietary adjustments, pharmacological treatments, and immunomodulatory therapies, represent promising approaches to counteract immunosenescence. These interventions aim to enhance immune function by improving the activity and interactions of aging-affected immune cells, or by modulating inflammatory responses through the suppression of excessive cytokine secretion and inflammatory pathway activation. Such strategies have the potential to restore immune homeostasis and mitigate age-related inflammation, thus reducing the risk of chronic diseases linked to aging. In summary, this review provides insights into the effects and underlying mechanisms of immunosenescence, as well as its potential interventions, with particular emphasis on the relationship between aging, immunity, and nutritional factors.
    Keywords:  aging; diet intervention; immune system; immunosenescence; immunotherapy
    DOI:  https://doi.org/10.3390/nu16223830
  19. Biomedicines. 2024 Nov 07. pii: 2540. [Epub ahead of print]12(11):
    The Quest for Eternal Youth: Hallmarks of Aging and Rejuvenating Therapeutic Strategies.
    Vharoon Sharma Nunkoo, Alexander Cristian, Anamaria Jurcau, Razvan Gabriel Diaconu, Maria Carolina Jurcau.
      The impressive achievements made in the last century in extending the lifespan have led to a significant growth rate of elderly individuals in populations across the world and an exponential increase in the incidence of age-related conditions such as cardiovascular diseases, diabetes mellitus type 2, and neurodegenerative diseases. To date, geroscientists have identified 12 hallmarks of aging (genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, impaired macroautophagy, mitochondrial dysfunction, impaired nutrient sensing, cellular senescence, stem cell exhaustion, defective intercellular communication, chronic inflammation, and gut dysbiosis), intricately linked among each other, which can be targeted with senolytic or senomorphic drugs, as well as with more aggressive approaches such as cell-based therapies. To date, side effects seriously limit the use of these drugs. However, since rejuvenation is a dream of mankind, future research is expected to improve the tolerability of the available drugs and highlight novel strategies. In the meantime, the medical community, healthcare providers, and society should decide when to start these treatments and how to tailor them individually.
    Keywords:  aging; hallmarks of aging; neurodegeneration; rejuvenation; senolytics; senomorphics
    DOI:  https://doi.org/10.3390/biomedicines12112540
  20. Nat Commun. 2024 Nov 27. 15(1): 10300
    Rab8a restores diverse innate functions in CD11c+CD11b+ dendritic cells from aged mice.
    Sudhakar Singh, Azeez Tehseen, Surbhi Dahiya, Yuviana J Singh, Roman Sarkar, Sharvan Sehrawat.
      Age-related alterations of the immune system compromise the host's ability to respond to pathogens, but how immune aging is regulated is still poorly understood. Here, we identify via transcriptomic analysis of splenic DCs and bone marrow derived dendritic cells (BMDC) of young and aged mice, the small GTPase Rab8a as a regulator of dendritic cell (DC) functions in mice. CD11c+CD11b+ DCs of aged in comparison to young host exhibit a diminished type I IFN response upon viral stimulation and inefficiently present exogenous antigens to CD8+ T cells in vitro and in vivo. Rab8a overexpression, which is accompanied by the upregulation of Rab11, restores the functionality of these aged DCs, whereas knockdown of Rab8a reduces functionality of DCs from young mice. Mechanistically, Rab8a and Rab11 cooperate to induce efficient trafficking of peptide loaded class I MHC molecules from the ER to the cell surface. We propose that targeting Rab8a might serve as a strategy to restore DC functionality in the context of immune aging.
    DOI:  https://doi.org/10.1038/s41467-024-54757-2
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