bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2023–05–07
fiveteen papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Tissue- and temporal-specific roles of extracellular ATP on T cell metabolism and function.
  2. Exhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities.
  3. Extremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging.
  4. Pannexin-1 channels promote CD8 + T cell effector and memory responses through distinct intracellular pathways.
  5. Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells.
  6. Acetate regulates GAPDH acetylation and T helper 1 cell differentiation.
  7. Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1.
  8. Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control.
  9. Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.
  10. Characterization of transitional memory CD4+ and CD8+ T-cell mobilization during and after an acute bout of exercise.
  11. In Vitro Modeling of CD8 T Cell Exhaustion Enables CRISPR Screening to Reveal a Role for BHLHE40.
  12. CD4+ T cell memory is impaired by species-specific cytotoxic differentiation, but not by TCF-1 loss.
  13. Editorial: Revisiting the thymus: the origin of T cells.
  14. Personality and aging-related immune phenotype.
  15. In Situ Vaccination with Mitochondria-Targeting Immunogenic Death Inducer Elicits CD8+ T Cell-Dependent Antitumor Immunity to Boost Tumor Immunotherapy.
  1. Immunometabolism (Cobham). 2023 Apr;5(2): e00025
    Tissue- and temporal-specific roles of extracellular ATP on T cell metabolism and function.
    Igor Santiago-Carvalho, Alma Banuelos, Henrique Borges da Silva.
      The activation and function of T cells is fundamental for the control of infectious diseases and cancer, and conversely can mediate several autoimmune diseases. Among the signaling pathways leading to T cell activation and function, the sensing of extracellular adenosine triphosphate (eATP) has been recently appreciated as an important component. Through a plethora of purinergic receptors, most prominently P2RX7, eATP sensing can induce a wide variety of processes in T cells, such as proliferation, subset differentiation, survival, or cell death. The downstream roles of eATP sensing can vary according to (a) the T cell subset, (b) the tissue where T cells are, and (c) the time after antigen exposure. In this mini-review, we revisit the recent findings on how eATP signaling pathways regulate T-cell immune responses and posit important unanswered questions on this field.
    Keywords:  P2RX7; T cell memory; T cells; eATP receptors; tissue damage
    DOI:  https://doi.org/10.1097/IN9.0000000000000025
  2. Front Immunol. 2023 ;14 1151632
    Exhausted T cells hijacking the cancer-immunity cycle: Assets and liabilities.
    Anna E Brunell, Riitta Lahesmaa, Anu Autio, Anil K Thotakura.
      T cell exhaustion is an alternative differentiation path of T cells, sometimes described as a dysfunction. During the last decade, insights of T cell exhaustion acting as a bottle neck in the field of cancer immunotherapy have undoubtedly provoked attention. One of the main drivers of T cell exhaustion is prolonged antigen presentation, a prerequisite in the cancer-immunity cycle. The umbrella term "T cell exhaustion" comprises various stages of T cell functionalities, describing the dynamic, one-way exhaustion process. Together these qualities of T cells at the exhaustion continuum can enable tumor clearance, but if the exhaustion acquired timeframe is exceeded, tumor cells have increased possibilities of escaping immune system surveillance. This could be considered a tipping point where exhausted T cells switch from an asset to a liability. In this review, the contrary role of exhausted T cells is discussed.
    Keywords:  T cell dysfunction; T cell exhaustion; cancer-immunity cycle; functional adaption; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2023.1151632
  3. Annu Rev Immunol. 2023 04 26. 41 181-205
    Extremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging.
    Gonzalo Soto-Heredero, Manuel M Gómez de Las Heras, J Ignacio Escrig-Larena, María Mittelbrunn.
      There is a dramatic remodeling of the T cell compartment during aging. The most notorious changes are the reduction of the naive T cell pool and the accumulation of memory-like T cells. Memory-like T cells in older people acquire a phenotype of terminally differentiated cells, lose the expression of costimulatory molecules, and acquire properties of senescent cells. In this review, we focus on the different subsets of age-associated T cells that accumulate during aging. These subsets include extremely cytotoxic T cells with natural killer properties, exhausted T cells with altered cytokine production, and regulatory T cells that gain proinflammatory features. Importantly, all of these subsets lose their lymph node homing capacity and migrate preferentially to nonlymphoid tissues, where they contribute to tissue deterioration and inflammaging.
    Keywords:  immunosenescence; inflammation; lymphocyte; senescence; thymus involution
    DOI:  https://doi.org/10.1146/annurev-immunol-101721-064501
  4. bioRxiv. 2023 Apr 21. pii: 2023.04.19.537580. [Epub ahead of print]
    Pannexin-1 channels promote CD8 + T cell effector and memory responses through distinct intracellular pathways.
    Trupti Vardam-Kaur, Alma Banuelos, Maria Gabaldon-Parish, Kelsey Marie Wanhainen, Maggie Hanqi Zhou, Sarah van Dijk, Bruna Gois Macedo, Caio Loureiro Salgado, Igor Santiago-Carvalho, Changwei Peng, Stephen C Jameson, Henrique Borges da Silva.
      Sensing of extracellular metabolites controls CD8 + T cell function. Their accumulation can occur through export by specialized molecules, such as the release channel Pannexin-1 (Panx1). Whether Panx1 controls CD8 + T cell immune responses to antigen, however, has not been previously addressed. Here, we report that T cell-specific Panx1 is needed for CD8 + T cell responses to viral infections and cancer. We found that CD8-specific Panx1 favors memory CD8 + T cell survival primarily through ATP export and induction of mitochondrial metabolism. CD8-specific Panx1 is also crucial for the effector expansion of CD8 + T cells, however this regulation occurs independently of eATP. Instead, our results suggest a connection between Panx1-induced extracellular lactate accumulation and the complete activation of effector CD8 + T cells. In summary, Panx1 regulates effector and memory CD8 + T cells through export of distinct metabolites and by engaging different metabolic and signaling pathways.
    DOI:  https://doi.org/10.1101/2023.04.19.537580
  5. Nat Commun. 2023 May 05. 14(1): 2593
    Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells.
    Mahesh Pandit, Yun-Seo Kil, Jae-Hee Ahn, Ram Hari Pokhrel, Ye Gu, Sunil Mishra, Youngjoo Han, Yung-Taek Ouh, Ben Kang, Myeong Seon Jeong, Jong-Oh Kim, Joo-Won Nam, Hyun-Jeong Ko, Jae-Hoon Chang.
      Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.
    DOI:  https://doi.org/10.1038/s41467-023-38316-9
  6. Mol Biol Cell. 2023 May 03. mbcE23020070
    Acetate regulates GAPDH acetylation and T helper 1 cell differentiation.
    Xizhong Jing, Junfang Lyu, Jianhua Xiong.
      The short-chain fatty acid metabolite acetyl-coenzyme A (acetyl-CoA) has emerged as a major signal transducer that can broadly affect cell fate and function at least partly by influencing acetylation of key proteins. The mechanism by which acetyl-CoA regulates CD4+ T cell fate determination remains poorly understood. Herein, we report that acetate modulates glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acetylation and CD4+ T helper 1 (Th1) cell differentiation by altering acetyl-CoA levels. Our transcriptome profiling shows that acetate is a robust positive regulator of CD4+ T cell gene expression typical of glycolysis. We further show that acetate potentiates GAPDH activity, aerobic glycolysis and Th1 polarization through regulation of GAPDH acetylation levels. This acetate-dependent GAPDH acetylation occurs in a dose- and time-dependent manner, while decreasing acetyl-CoA levels by fatty acid oxidation (FAO) inhibition results in a decline in acetyl-GAPDH levels. Thus, acetate functions as a potent metabolic regulator in CD4+ T cells by promoting GAPDH acetylation and Th1 cell fate decision.
    DOI:  https://doi.org/10.1091/mbc.E23-02-0070
  7. Biomed Pharmacother. 2023 May 02. pii: S0753-3322(23)00614-5. [Epub ahead of print]163 114824
    Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1.
    Keywan Mortaezaee, Jamal Majidpoor.
      CD8+ T cells are the front-line defensive cells against cancer. Reduced infiltration and effector function of CD8+ T cells occurs in cancer and is contributed to defective immunity and immunotherapy resistance. Exclusion and exhaustion of CD8+ T cells are the two key factors associated with reduced durability of immune checkpoint inhibitor (ICI) therapy. Initially activated T cells upon exposure to chronic antigen stimulation or immunosuppressive tumor microenvironment (TME) acquire a hyporesponsive state that progressively lose their effector function. Thus, a key strategy in cancer immunotherapy is to look for factors contributed to defective CD8+ T cell infiltration and function. Targeting such factors can define a promising supplementary approach in patients receiving anti-programmed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy. Recently, bispecific antibodies are developed against PD-(L)1 and a dominant factor within TME, representing higher safety profile and exerting more desired outcomes. The focus of this review is to discuss about promoters of deficient infiltration and effector function of CD8+ T cells and their addressing in cancer ICI therapy.
    Keywords:  CD8(+) T cell; Exhaustion; Immune checkpoint inhibitor (ICI); Programmed death-1 receptor (PD-1); Programmed death-ligand 1 (PD-L1); Resistance
    DOI:  https://doi.org/10.1016/j.biopha.2023.114824
  8. bioRxiv. 2023 Apr 17. pii: 2023.04.15.536946. [Epub ahead of print]
    Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control.
    Mengdi Guo, Diala Abd-Rabbo, Bruna Bertol, Madeleine Carew, Sabelo Lukhele, Laura M Snell, Wenxi Xu, Giselle M Boukhaled, Heidi Elsaesser, Marie Jo Halaby, Naoto Hirano, Tracy L McGaha, David G Brooks.
      CD4 T cells are important effectors of anti-tumor immunity, yet the regulation of CD4 tumor-specific T (T TS ) cells during cancer development is still unclear. We demonstrate that CD4 T TS cells are initially primed in the tumor draining lymph node and begin to divide following tumor initiation. Distinct from CD8 T TS cells and previously defined exhaustion programs, CD4 T TS cell proliferation is rapidly frozen in place and differentiation stunted by a functional interplay of T regulatory cells and both intrinsic and extrinsic CTLA4 signaling. Together these mechanisms paralyze CD4 T TS cell differentiation, redirecting metabolic and cytokine production circuits, and reducing CD4 T TS cell accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 T TS cells rapidly resume proliferation and functional differentiation when both suppressive reactions are alleviated. Strikingly, Treg depletion alone reciprocally induced CD4 T TS cells to themselves become tumor-specific Tregs, whereas CTLA4 blockade alone failed to promote T helper differentiation. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 T TS cells to favor tumor progression.
    DOI:  https://doi.org/10.1101/2023.04.15.536946
  9. Nature. 2023 May 03.
    Targeting PD-L2-RGMb overcomes microbiome-related immunotherapy resistance.
    Joon Seok Park, Francesca S Gazzaniga, Meng Wu, Amalia K Luthens, Jacob Gillis, Wen Zheng, Martin W LaFleur, Sarah B Johnson, Golnaz Morad, Elizabeth M Park, Yifan Zhou, Stephanie S Watowich, Jennifer A Wargo, Gordon J Freeman, Dennis L Kasper, Arlene H Sharpe.
      The gut microbiota is a crucial regulator of anti-tumour immunity during immune checkpoint inhibitor therapy. Several bacteria that promote an anti-tumour response to immune checkpoint inhibitors have been identified in mice1-6. Moreover, transplantation of faecal specimens from responders can improve the efficacy of anti-PD-1 therapy in patients with melanoma7,8. However, the increased efficacy from faecal transplants is variable and how gut bacteria promote anti-tumour immunity remains unclear. Here we show that the gut microbiome downregulates PD-L2 expression and its binding partner repulsive guidance molecule b (RGMb) to promote anti-tumour immunity and identify bacterial species that mediate this effect. PD-L1 and PD-L2 share PD-1 as a binding partner, but PD-L2 can also bind RGMb. We demonstrate that blockade of PD-L2-RGMb interactions can overcome microbiome-dependent resistance to PD-1 pathway inhibitors. Antibody-mediated blockade of the PD-L2-RGMb pathway or conditional deletion of RGMb in T cells combined with an anti-PD-1 or anti-PD-L1 antibody promotes anti-tumour responses in multiple mouse tumour models that do not respond to anti-PD-1 or anti-PD-L1 alone (germ-free mice, antibiotic-treated mice and even mice colonized with stool samples from a patient who did not respond to treatment). These studies identify downregulation of the PD-L2-RGMb pathway as a specific mechanism by which the gut microbiota can promote responses to PD-1 checkpoint blockade. The results also define a potentially effective immunological strategy for treating patients who do not respond to PD-1 cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-023-06026-3
  10. Front Sports Act Living. 2023 ;5 1120454
    Characterization of transitional memory CD4+ and CD8+ T-cell mobilization during and after an acute bout of exercise.
    Rebekah M Hunt, Mahmoud T Elzayat, Melissa M Markofski, Mitzi Laughlin, Emily C LaVoy.
      T-cell subsets, including naïve (NA), central memory (CM), transitional memory (TM), effector memory (EM), and RA + effector memory (EMRA), differ in phenotype and function. T-cells are mobilized by exercise, with differences in the magnitude of mobilization between subsets. However, the response of TM T-cells to exercise has not yet been described. Further, T-cells expressing the late differentiation marker CD57 are known to be highly responsive to exercise, but the relative response of CD57 + and CD57- within T-cell subsets is unknown. We therefore aimed to characterize the exercise-induced mobilization of TM T-cells, as well as to compare the exercise response of CD57 + and CD57- cells within T-cell subsets.
    Methods: Seventeen participants (7 female; aged 18-40 years) cycled 30 min at 80% of their estimated maximum heart rate. Venous blood obtained pre, post, and 1H post-exercise was analyzed by flow cytometry. CD45RA, CCR7, and CD28 expression within CD4 + and CD8+ T-cells identified NA, CM, TM, EM, and EMRA subsets. CD57 expression within EM, EMRA, and CD28+ T-cells was also quantified. The relative mobilization of each subset was compared by calculating fold change in cell concentration during (ingress, post/pre) and after exercise (egress,1H post/post). Cytomegalovirus (CMV) serostatus was determined by ELISA and was considered in models.
    Results: TM CD8+ T-cell concentration was greater post-exercise than pre-exercise (138.59 ± 56.42 cells/µl vs. 98.51 ± 39.68 cells/µl, p < 0.05), and the proportion of CD8 + with a TM phenotype was elevated 1H post-exercise (1H: 32.44 ± 10.38% vs. Pre: 30.15 ± 8.77%, p < 0.05). The relative mobilization during and after exercise of TM T-cells did not differ from NA and CM but was less than EM and EMRA subsets. Similar results were observed within CD4+ T-cells. CD57 + subsets of CD28+ T-cells and of EM and EMRA CD8+ T-cells exhibited a greater relative mobilization than CD57- subsets (all p < 0.05).
    Conclusion: These results indicate TM CD4 + and CD8+ T-cells are transiently mobilized into the blood with exercise, but not to as great of an extent as later differentiated EM and EMRA T-cells. Results also indicate CD57 identifies highly exercise responsive cells within CD8+ T-cell subsets.
    Keywords:  exercise response; immunity; leukocyte differentiation; lymphocytes; physical activity
    DOI:  https://doi.org/10.3389/fspor.2023.1120454
  11. bioRxiv. 2023 Apr 17. pii: 2023.04.17.537229. [Epub ahead of print]
    In Vitro Modeling of CD8 T Cell Exhaustion Enables CRISPR Screening to Reveal a Role for BHLHE40.
    Jennifer E Wu, Sasikanth Manne, Shin Foong Ngiow, Amy E Baxter, Hua Huang, Elizabeth Freilich, Megan L Clark, Joanna H Lee, Zeyu Chen, Omar Khan, Ryan P Staupe, Yinghui J Huang, Junwei Shi, Josephine R Giles, E John Wherry.
      Identifying novel molecular mechanisms of exhausted CD8 T cells (T ex ) is a key goal of improving immunotherapy of cancer and other diseases. However, high-throughput interrogation of in vivo T ex can be costly and inefficient. In vitro models of T ex are easily customizable and quickly generate high cellular yield, offering an opportunity to perform CRISPR screening and other high-throughput assays. We established an in vitro model of chronic stimulation and benchmarked key phenotypic, functional, transcriptional, and epigenetic features against bona fide in vivo T ex . We leveraged this model of in vitro chronic stimulation in combination with pooled CRISPR screening to uncover transcriptional regulators of T cell exhaustion. This approach identified several transcription factors, including BHLHE40. In vitro and in vivo validation defined a role for BHLHE40 in regulating a key differentiation checkpoint between progenitor and intermediate subsets of T ex . By developing and benchmarking an in vitro model of T ex , we demonstrate the utility of mechanistically annotated in vitro models of T ex , in combination with high-throughput approaches, as a discovery pipeline to uncover novel T ex biology.
    DOI:  https://doi.org/10.1101/2023.04.17.537229
  12. Front Immunol. 2023 ;14 1168125
    CD4+ T cell memory is impaired by species-specific cytotoxic differentiation, but not by TCF-1 loss.
    Tom Hofland, Luca Danelli, Georgina Cornish, Tiziano Donnarumma, Deborah M Hunt, Luiz P S de Carvalho, George Kassiotis.
      CD4+ T cells are typically considered as 'helper' or 'regulatory' populations that support and orchestrate the responses of other lymphocytes. However, they can also develop potent granzyme (Gzm)-mediated cytotoxic activity and CD4+ cytotoxic T cells (CTLs) have been amply documented both in humans and in mice, particularly in the context of human chronic infection and cancer. Despite the established description of CD4+ CTLs, as well as of the critical cytotoxic activity they exert against MHC class II-expressing targets, their developmental and memory maintenance requirements remain elusive. This is at least in part owing to the lack of a murine experimental system where CD4+ CTLs are stably induced. Here, we show that viral and bacterial vectors encoding the same epitope induce distinct CD4+ CTL responses in challenged mice, all of which are nevertheless transient in nature and lack recall properties. Consistent with prior reports, CD4+ CTL differentiation is accompanied by loss of TCF-1 expression, a transcription factor considered essential for memory T cell survival. Using genetic ablation of Tcf7, which encodes TCF-1, at the time of CD4+ T cell activation, we further show that, contrary to observations in CD8+ T cells, continued expression of TCF-1 is not required for CD4+ T cell memory survival. Whilst Tcf7-deficient CD4+ T cells persisted normally following retroviral infection, the CD4+ CTL subset still declined, precluding conclusive determination of the requirement for TCF-1 for murine CD4+ CTL survival. Using xenotransplantation of human CD4+ T cells into murine recipients, we demonstrate that human CD4+ CTLs develop and persist in the same experimental conditions where murine CD4+ CTLs fail to persist. These observations uncover a species-specific defect in murine CD4+ CTL persistence with implications for their use as a model system.
    Keywords:  CD4 T cell; TCF-1; granzyme B (GzmB); human; immunological memory; mouse
    DOI:  https://doi.org/10.3389/fimmu.2023.1168125
  13. Front Immunol. 2023 ;14 1197066
    Editorial: Revisiting the thymus: the origin of T cells.
    Xiaoxi Lin, Yayi Gao, Yi Ding, Bin Zhao.
      
    Keywords:  T cell development; T cell differentiation; T cell signaling; thymocyte; thymus
    DOI:  https://doi.org/10.3389/fimmu.2023.1197066
  14. Psychoneuroendocrinology. 2023 Apr 17. pii: S0306-4530(23)00091-4. [Epub ahead of print]153 106113
    Personality and aging-related immune phenotype.
    Yannick Stephan, Angelina R Sutin, Martina Luchetti, Damaris Aschwanden, Antonio Terracciano.
      An aging-related immune phenotype (ARIP) has been defined as a decrease in naïve T cells (TN) relative to the accumulation of memory T cells (TM). Recent research implicates ARIP measures, such as CD4 +TN/TM and CD8 +TN/TM ratios, in multimorbidity and mortality. This study examined whether psychological dispositions that assess how people think, feel, and behave are related to CD4 +TN/TM and CD8 +TN/TM. Participants were adults aged 50-104 years (N = 4798; 58% women, Mean Age= 67.95, SD= 9.56) from the Health and Retirement Study. Data on CD4 +TN/TM and CD8 +TN/TM were obtained in 2016. Data on personality, demographic factors, and potential clinical (body mass index, disease burden), behavioral (smoking, alcohol, physical activity), psychological (depressive symptoms, stress), and biological (cytomegalovirus IgG antibodies) mediating factors were obtained in 2014/2016. Controlling for demographic factors, higher conscientiousness was related to higher CD4 +TN/TM and CD8 +TN/TM. To a lesser extent, higher neuroticism and lower extraversion were associated with lower CD4 +TN/TM. Physical activity, and to a lesser extent BMI and disease burden, were the most robust mediators between personality and ARIP measures. Cytomegalovirus IgG level mediated the association between conscientiousness and both CD4 +TN/TM and CD8 +TN/TM. This study provides novel evidence that personality is related to ARIP. Higher conscientiousness and, to a lesser extent, higher extraversion may be protective against age-related immunophenotype change, whereas neuroticism may be a risk factor.
    Keywords:  Age-related immunophenotype change; Personality; T-cells
    DOI:  https://doi.org/10.1016/j.psyneuen.2023.106113
  15. Adv Sci (Weinh). 2023 May 01. e2300286
    In Situ Vaccination with Mitochondria-Targeting Immunogenic Death Inducer Elicits CD8+ T Cell-Dependent Antitumor Immunity to Boost Tumor Immunotherapy.
    Yuxiang Wang, Weiran Wang, Rong Gu, Jing Chen, Qian Chen, Tingsheng Lin, Jinhui Wu, Yiqiao Hu, Ahu Yuan.
      In situ vaccination can elicit systemic antitumor immunity to potentiate immune checkpoint blockade (ICB) in poorly immunogenic tumors. Herein, an immunogenic cell death (ICD) inducer for in situ vaccination, which is based on a mitochondria-targeting modification of fenofibric acid (FFa), a lipid-lowering drug with potential inhibitory efficacy of respiratory complex I is developed. Mitochondria-targeting FFa (Mito-FFa) inhibits complex I efficiently and increases mitochondrial ROS (mtROS) generation, which further triggers endoplasmic reticulum (ER) stress with unprecedented calreticulin (CRT) exposure on tumor cellular membranes. Moreover, the generated mtROS also oxidizes mitochondrial DNA (mtDNA) and promotes it leakage into the cytoplasm for cGAS-STING-dependent type I interferon (IFN-I) secretion. The synchronous CRT exposure and IFN-I secretion successively improve the uptake of tumor antigens, maturation of dendritic cells (DCs) and cross-priming of CD8+ T cells. In a poorly immunogenic 4T1 tumor model, a single intratumoral (i.t.) Mito-FFa injection turns immune-cold tumors into hot ones and elicits systemic tumor-specific CD8+ T cells responses against primary and metastatic tumors. Furthermore, the synergistic effect with PD-L1 blockade and good bio-safety of i.t. Mito-FFa administration suggest the great translational potential of Mito-FFa in tumor immunotherapy.
    Keywords:  calreticulin; immunogenic cell death; in situ tumor vaccination; mitochondria-targeting; type I interferon
    DOI:  https://doi.org/10.1002/advs.202300286
This page is being maintained by Thomas Krichel. It was last updated on 2024‒11‒22 at 4:17.