bims-imseme 2023-03-19 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023‒03‒19
fourteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

Metabolic Challenges in Anticancer CD8 T Cell Functions.
Exhausted CD8+ T cells face a developmental fork in the road.
Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells.
Shaping Heterogeneity of Naive CD8+ T Cell Pools.
Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: Contributions to pathogenesis and clinical applications.
Intrinsic RIG-I restrains STAT5 activation to modulate anti-tumor activity of CD8+ T cells.
Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells.
NFκB signaling in T cell memory.
Active maintenance of CD8 + T cell naïvety through regulation of global genome architecture.
The dietary sweetener sucralose is a negative modulator of T cell-mediated responses.
Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.
Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection.
Galectin-3 expression in donor T cells reduces GvHD severity and lethality after allogeneic hematopoietic cell transplantation.
Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes.

Immune Netw. 2023 Feb;23(1): e9

Metabolic Challenges in Anticancer CD8 T Cell Functions.

Andrea M Amitrano, Minsoo Kim.

  Cancer immunotherapies continue to face numerous obstacles in the successful treatment of solid malignancies. While immunotherapy has emerged as an extremely effective treatment option for hematologic malignancies, it is largely ineffective against solid tumors due in part to metabolic challenges present in the tumor microenvironment (TME). Tumor-infiltrating CD8+ T cells face fierce competition with cancer cells for limited nutrients. The strong metabolic suppression in the TME often leads to impaired T-cell recruitment to the tumor site and hyporesponsive effector functions via T-cell exhaustion. Growing evidence suggests that mitochondria play a key role in CD8+ T-cell activation, migration, effector functions, and persistence in tumors. Therefore, targeting the mitochondrial metabolism of adoptively transferred T cells has the potential to greatly improve the effectiveness of cancer immunotherapies in treating solid malignancies.

Keywords:  CD8 Positive T lymphocytes; Chimeric antigen receptor therapy; Metabolism; Mitochondria

DOI:  https://doi.org/10.4110/in.2023.23.e9
Trends Immunol. 2023 Mar 11. pii: S1471-4906(23)00031-5. [Epub ahead of print]

Exhausted CD8+ T cells face a developmental fork in the road.

Ryan Zander, Weiguo Cui.

Reinvigorating the function of exhausted CD8+ T cells during chronic viral infection and cancer is a major goal of current immunotherapy regimens. Here, we discuss recent advances in our understanding of exhausted CD8+ T cell heterogeneity as well as the potential differentiation trajectories that exhausted T cells follow during chronic infection and/or cancer. We highlight surmounting evidence suggesting that some T cell clones are divergent in nature and can develop into either terminally differentiated effector or exhausted CD8+ T cells. Lastly, we consider the potential therapeutic implications of such a bifurcation model of CD8+ T cell differentiation, including the intriguing hypothesis that redirecting progenitor CD8+ T cell differentiation along an effector pathway may serve as a novel approach to mitigate T cell exhaustion.

DOI: https://doi.org/10.1016/j.it.2023.02.006
Proc Natl Acad Sci U S A. 2023 Mar 21. 120(12): e2218632120

Combined disruption of T cell inflammatory regulators Regnase-1 and Roquin-1 enhances antitumor activity of engineered human T cells.

David Mai, Omar Johnson, Jordan Reff, Ting-Jia Fan, John Scholler, Neil C Sheppard, Carl H June.

  A fundamental limitation of T cell therapies in solid tumors is loss of inflammatory effector functions, such as cytokine production and proliferation. Here, we target a regulatory axis of T cell inflammatory responses, Regnase-1 and Roquin-1, to enhance antitumor responses in human T cells engineered with two clinical-stage immune receptors. Building on previous observations of Regnase-1 or Roquin-1 knockout in murine T cells or in human T cells for hematological malignancy models, we found that knockout of either Regnase-1 or Roquin-1 alone enhances antitumor function in solid tumor models, but that knockout of both Regnase-1 and Roquin-1 increases function further than knockout of either regulator alone. Double knockout of Regnase-1 and Roquin-1 increased resting T cell inflammatory activity and led to at least an order of magnitude greater T cell expansion and accumulation in xenograft mouse models, increased cytokine activity, and persistence. However double knockout of Regnase-1 and Roguin-1 also led to a lymphoproliferative syndrome and toxicity in some mice. These results suggest that regulators of immune inflammatory functions may be interesting targets to modulate to improve antitumor responses.

Keywords:  T cell therapy; gene editing; inflammation; solid tumors

DOI:  https://doi.org/10.1073/pnas.2218632120
Immune Netw. 2023 Feb;23(1): e2

Shaping Heterogeneity of Naive CD8+ T Cell Pools.

Sung-Woo Lee, Gil-Woo Lee, Hee-Ok Kim, Jae-Ho Cho.

  Immune diversification helps protect the host against a myriad of pathogens. CD8+ T cells are essential adaptive immune cells that inhibit the spread of pathogens by inducing apoptosis in infected host cells, ultimately ensuring complete elimination of infectious pathogens and suppressing disease development. Accordingly, numerous studies have been conducted to elucidate the mechanisms underlying CD8+ T cell activation, proliferation, and differentiation into effector and memory cells, and to identify various intrinsic and extrinsic factors regulating these processes. The current knowledge accumulated through these studies has led to a huge breakthrough in understanding the existence of heterogeneity in CD8+ T cell populations during immune response and the principles underlying this heterogeneity. As the heterogeneity in effector/memory phases has been extensively reviewed elsewhere, in the current review, we focus on CD8+ T cells in a "naïve" state, introducing recent studies dealing with the heterogeneity of naive CD8+ T cells and discussing the factors that contribute to such heterogeneity. We also discuss how this heterogeneity contributes to establishing the immense complexity of antigen-specific CD8+ T cell response.

Keywords:  Cytokine; Heterogeneity; Homeostasis; Naive T-cell; Self-antigen

DOI:  https://doi.org/10.4110/in.2023.23.e2
Lupus. 2023 Mar 13. 9612033231164635

Mitochondrial bioenergetic changes in systemic lupus erythematosus immune cell subsets: Contributions to pathogenesis and clinical applications.

Anjali S Yennemadi, Joseph Keane, Gina Leisching.

  The association of dysregulated metabolism in systemic lupus erythematosus (SLE) pathogenesis has prompted investigations into metabolic rewiring and the involvement of mitochondrial metabolism as a driver of disease through NLRP3 inflammasome activation, disruption of mitochondrial DNA maintenance, and pro-inflammatory cytokine release. The use of Agilent Seahorse Technology to gain functional in situ metabolic insights of selected cell types from SLE patients has identified key parameters that are dysregulated during disease. Mitochondrial functional assessments specifically can detect dysfunction through oxygen consumption rate (OCR), spare respiratory capacity, and maximal respiration measurements, which, when coupled with disease activity scores could show potential as markers of disease activity. CD4+ and CD8 + T cells have been assessed in this way and show that oxygen consumption rate, spare respiratory capacity, and maximal respiration are blunted in CD8 + T cells, with results not being as clear cut in CD4 + T cells. Additionally, glutamine, processed by mitochondrial substrate level phosphorylation is emerging as a key role player in the expansion and differentiation of Th1, Th17, ϒδ T cells, and plasmablasts. The role that circulating leukocytes play in acting as bioenergetic biomarkers of diseases such as diabetes suggests that this may also be a tool to detect preclinical SLE. Therefore, the metabolic characterization of immune cell subsets and the collection of metabolic data during interventions is also essential. The delineation of the metabolic tuning of immune cells in this way could lead to novel strategies in treating metabolically demanding processes characteristic of autoimmune diseases such as SLE.

Keywords:  Systemic lupus erythematosus; autoimmunity; glutamate; glutamine; glycolysis; immunometabolism; inflammation; mitochondria; oxygen consumption rate (OCR); substrate level phosphorylation

DOI:  https://doi.org/10.1177/09612033231164635
J Clin Invest. 2023 Mar 16. pii: e160790. [Epub ahead of print]

Intrinsic RIG-I restrains STAT5 activation to modulate anti-tumor activity of CD8+ T cells.

Xinyi Jiang, Jian Lin, Chengfang Shangguan, Xiaoyao Wang, Bin Xiang, Juan Chen, Hezhou Guo, Wu Zhang, Jun Zhang, Yan Shi, Jiang Zhu, Hui Yang.

  Anti-tumor activity of CD8+ T cells is potentially restrained by a variety of negative regulatory pathways that are triggered in tumor microenvironment, yet exact mechanisms remain incompletely defined. Here we report that intrinsic RIG-I in CD8+ T cells represents such a factor, as evidenced by observations that tumor-restricting effect of endogenous or adoptively transferred CD8+ T cells was enhanced by intrinsic Rig-I deficiency or inhibition, with the increased accumulation, survival, and cytotoxicity of tumor-infiltrating CD8+ T cells. Mechanistically, T cell activation-induced RIG-I upregulation restrained STAT5 activation via competitively sequestering HSP90. In accordance, the frequency of RIG-I+ tumor-infiltrating CD8+ T cells in human colon cancer positively correlated with attenuated survival and effector signatures of CD8+ T cells as well as poor prognosis. Collectively, these results implicate RIG-I as a potentially druggable factor for improving CD8+ T cells-based tumor immunotherapy.

Keywords:  Colorectal cancer; Immunology; Immunotherapy; Oncology; T cells

DOI:  https://doi.org/10.1172/JCI160790
Front Immunol. 2023 ;14 1101433

Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells.

Laura Barbieri, Pedro Veliça, Paulo A Gameiro, Pedro P Cunha, Iosifina P Foskolou, Eric Rullman, David Bargiela, Randall S Johnson, Helene Rundqvist.

  Introduction: CD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in local tissues can result in significant exposure of cytotoxic T cells to the lactate metabolite. Lactate has been known to act as an immunosuppressor, at least in part due to its association with tissue acidosis.Methods: To dissect the role of the lactate anion, independently of pH, we performed phenotypical and metabolic assays, high-throughput RNA sequencing, and mass spectrometry, on primary cultures of murine or human CD8+ T cells exposed to high doses of pH-neutral sodium lactate.
Results: The lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and can displace glucose as a carbon source. Activation in the presence of sodium lactate significantly alters the CD8+ T cell transcriptome, including the expression key effector differentiation markers such as granzyme B and interferon-gamma.
Discussion: Our studies reveal novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells.

Keywords:  CD8+ T cells; lactate; metabolism; oxygen; transcriptome

DOI:  https://doi.org/10.3389/fimmu.2023.1101433
Front Immunol. 2023 ;14 1129191

NFκB signaling in T cell memory.

Mark A Daniels, Dezzarae Luera, Emma Teixeiro.

  Memory T cells play an essential role in protecting against infectious diseases and cancer and contribute to autoimmunity and transplant rejection. Understanding how they are generated and maintained in the context of infection or vaccination holds promise to improve current immune-based therapies. At the beginning of any immune response, naïve T cells are activated and differentiate into cells with effector function capabilities. In the context of infection, most of these cells die once the pathogenic antigen has been cleared. Only a few of them persist and differentiate into memory T cells. These memory T cells are essential to host immunity because they are long-lived and can perform effector functions immediately upon re-infection. How a cell becomes a memory T cell and continues being one for months and even years past the initial infection is still not fully understood. Recent reviews have thoroughly discussed the transcriptional, epigenomic, and metabolic mechanisms that govern T cell memory differentiation. Yet much less is known of how signaling pathways that are common circuitries of multiple environmental signals regulate T cell outcome and, precisely, T cell memory. The function of the NFκB signaling system is perhaps best understood in innate cells. Recent findings suggest that NFκB signaling plays an essential and unique role in generating and maintaining CD8 T cell memory. This review aims to summarize these findings and discuss the remaining questions in the field.

Keywords:  NFκB signaling; T cell memory; environmental cues; immunological memory; protective immunity

DOI:  https://doi.org/10.3389/fimmu.2023.1129191
bioRxiv. 2023 Feb 27. pii: 2023.02.26.530139. [Epub ahead of print]

Active maintenance of CD8 + T cell naïvety through regulation of global genome architecture.

Brendan E Russ, Kirril Tsyganov, Sara Quon, Bingfei Yu, Jasmine Li, Jason K C Lee, Moshe Olshansky, Zhaohren He, Paul F Harrison, Adele Barugahare, Michael See, Simone Nussing, Alison E Morey, Vibha A Udupa, Taylah J Bennett, Axel Kallies, Cornelis Murre, Phillipe Collas, David Powell, Ananda W Goldrath, Stephen J Turner.

The differentiation of naïve CD8 + cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naïve, effector and memory virus-specific CD8 + T cells. We observed that the architecture of the naive CD8 + T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naïve chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naïve CD8 + T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naïve chromatin state.One Sentence Summary: CD8 + T cell naïvety is actively maintained by transcription factors that enforce a distinct, naïve chromatin architecture.
Highlights: CD8 + T cell differentiation states are underscored by distinct chromatin looping architectures. Chromatin loops juxtapose CTL state appropriate enhancers, transcription factors and genes.Effector and memory CTLs have similar genome architectures, explaining rapid memory recall.CTL differentiation is restrained by BACH2 and SATB1, which enforce a naïve loop architecture.

DOI: https://doi.org/10.1101/2023.02.26.530139
Nature. 2023 Mar 15.

The dietary sweetener sucralose is a negative modulator of T cell-mediated responses.

Fabio Zani, Julianna Blagih, Tim Gruber, Michael D Buck, Nicholas Jones, Marc Hennequart, Clare L Newell, Steven E Pilley, Pablo Soro-Barrio, Gavin Kelly, Nathalie M Legrave, Eric C Cheung, Ian S Gilmore, Alex P Gould, Cristina Garcia-Caceres, Karen H Vousden.

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years1. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners2-5. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8+ T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders.

DOI: https://doi.org/10.1038/s41586-023-05801-6
J Immunother Cancer. 2023 03;pii: e006522. [Epub ahead of print]11(3):

Metabolic reprogramming via an engineered PGC-1α improves human chimeric antigen receptor T-cell therapy against solid tumors.

Konstantinos Lontos, Yiyang Wang, Supriya K Joshi, Andrew T Frisch, McLane J Watson, Alok Kumar, Ashley V Menk, Yupeng Wang, Rachel Cumberland, Jason Lohmueller, Esteban Carrizosa, Benjamin Boyerinas, Greg M Delgoffe.

  BACKGROUND: Cellular immunotherapies for cancer represent a means by which a patient's immune system can be augmented with high numbers of tumor-specific T cells. Chimeric antigen receptor (CAR) therapy involves genetic engineering to 'redirect' peripheral T cells to tumor targets, showing remarkable potency in blood cancers. However, due to several resistance mechanisms, CAR-T cell therapies remain ineffective in solid tumors. We and others have shown the tumor microenvironment harbors a distinct metabolic landscape that produces a barrier to immune cell function. Further, altered differentiation of T cells within tumors induces defects in mitochondrial biogenesis, resulting in severe cell-intrinsic metabolic deficiencies. While we and others have shown murine T cell receptor (TCR)-transgenic cells can be improved through enhanced mitochondrial biogenesis, we sought to determine whether human CAR-T cells could be enabled through a metabolic reprogramming approach.MATERIALS AND METHODS: Anti-EGFR CAR-T cells were infused in NSG mice which bore A549 tumors. The tumor infiltrating lymphocytes were analyzed for exhaustion and metabolic deficiencies. Lentiviruses carrying PPAR-gamma coactivator 1α (PGC-1α), PGC-1αS571A and NT-PGC-1α constructs were used to co-transduce T cells with anti-EGFR CAR lentiviruses. We performed metabolic analysis via flow cytometry and Seahorse analysis in vitro as well as RNA sequencing. Finally, we treated therapeutically A549-carrying NSG mice with either PGC-1α or NT-PGC-1α anti-EGFR CAR-T cells. We also analyzed the differences in the tumor-infiltrating CAR-T cells when PGC-1α is co-expressed.
RESULTS: Here, in this study, we show that an inhibition resistant, engineered version of PGC-1α, can metabolically reprogram human CAR-T cells. Transcriptomic profiling of PGC-1α-transduced CAR-T cells showed this approach effectively induced mitochondrial biogenesis, but also upregulated programs associated with effector functions. Treatment of immunodeficient animals bearing human solid tumors with these cells resulted in substantially improved in vivo efficacy. In contrast, a truncated version of PGC-1α, NT-PGC-1α, did not improve the in vivo outcomes.
CONCLUSIONS: Our data further support a role for metabolic reprogramming in immunomodulatory treatments and highlight the utility of genes like PGC-1α as attractive candidates to include in cargo along with chimeric receptors or TCRs for cell therapy of solid tumors.

Keywords:  Cell Engineering; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Translational Medical Research

DOI:  https://doi.org/10.1136/jitc-2022-006522
Brain Behav Immun Health. 2023 May;29 100608

Premature T cell aging in major depression: A double hit by the state of disease and cytomegalovirus infection.

Maria S Simon, Magdalini Ioannou, Gara Arteaga-Henríquez, Annemarie Wijkhuijs, Raf Berghmans, Richard Musil, Norbert Müller, Hemmo A Drexhage.

  Introduction: Previous research indicates that premature T cell senescence is a characteristic of major depressive disorder (MDD). However, known senescence inducing factors like cytomegalovirus (CMV) infection or, probably, childhood adversity (CA) have not been taken into consideration so far.Objective: Differentiation and senescent characteristics of T cells of MDD patients were investigated in relation to healthy controls (HC), taking the CMV seropositivity and CA into account.
Methods: 127 MDD and 113 HC of the EU-MOODSTRATIFICATION cohort were analyzed. Fluorescence activated cell sorting (FACS) analysis was performed to determine B, NK, and T cell frequencies. In a second FACS analysis, naïve, effector memory (Tem), central memory (Tcm), effector memory cells re-expressing RA (TEMRA), as well as CD28+ and CD27+ memory populations, were determined of the CD4+ and CD8+ T cell populations in a subsample (N = 35 MDD and N = 36 HC). CMV-antibody state was measured by IgG ELISA and CA by the Childhood Trauma Questionnaire.
Results: We detected a CMV-antibody positivity in 40% of MDD patients (35% HC, n. s.) with seropositive MDD cases showing a higher total childhood trauma score. Second, a higher inflation of memory CD4+ T helper cells in CMV seronegative patients as compared to seronegative HC and reduced numbers of naïve CD4+ T helper cells in CMV seropositive patients (not in CMV seropositive HC) were found. Third, a higher inflation of memory CD8+ T cytotoxic cells in CMV seropositive cases as compared to CMV seropositive HC, particularly of the TEMRA cells, became apparent. Higher percentages of CD4+ TEMRA and late stage CD27-CD28- TEMRA cells were similar in both HC and MDD with CMV seropositivity. Overall, apportioning of T cell subpopulations did not differ between CA positive vs negative cases.
Conclusions: MDD patients show several signs of a CMV independent "MDD specific" premature T cell aging, such as a CMV independent increase in CD4+ T memory cells and a latent naïve CD4 T-cell reduction and a latent CD8+ T-cell increase. However, these two latent T cell senescence abnormalities only become evident with CMV infection (double hit).

Keywords:  CMV; Childhood trauma; Major depressive disorder; Senescence; T cytotoxic cell; T helper cell

DOI:  https://doi.org/10.1016/j.bbih.2023.100608
Cell Rep. 2023 Mar 15. pii: S2211-1247(23)00261-9. [Epub ahead of print]42(3): 112250

Galectin-3 expression in donor T cells reduces GvHD severity and lethality after allogeneic hematopoietic cell transplantation.

Hemn Mohammadpour, Takemasa Tsuji, Cameron R MacDonald, Joseph L Sarow, Hanna Rosenheck, Saeed Daneshmandi, Jee Eun Choi, Jingxin Qiu, Junko Matsuzaki, Agnieszka K Witkiewicz, Kristopher Attwood, Bruce R Blazar, Kunle Odunsi, Elizabeth A Repasky, Philip L McCarthy.

  Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT. In both major and minor histocompatibility-mismatched models of murine aGvHD, expression of Gal-3 is associated with decreased T cell activation and suppression of the secretion of effector cytokines, including IFN-γ and GM-CSF. Mechanistically, Gal-3 results in activation of NFAT signaling, which can induce T cell exhaustion. Gal-3 overexpression in human T cells prevents severe disease by suppressing cytotoxic T cells in xenogeneic aGvHD models. Together, these data identify the Gal-3-dependent regulatory pathway in donor T cells as a critical component of inflammation in aGvHD.

Keywords:  CP: Immunology; GI biopsies; NFAT; T cells; allogeneic hematopoietic cell transplantation; galectin-3; graft versus host disease; retroviral transduction

DOI:  https://doi.org/10.1016/j.celrep.2023.112250
Cell. 2023 Mar 16. pii: S0092-8674(23)00164-2. [Epub ahead of print]186(6): 1127-1143.e18

Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes.

Maha K Rahim, Trine Line H Okholm, Kyle B Jones, Elizabeth E McCarthy, Candace C Liu, Jacqueline L Yee, Stanley J Tamaki, Diana M Marquez, Iliana Tenvooren, Katherine Wai, Alexander Cheung, Brittany R Davidson, Vrinda Johri, Bushra Samad, William E O'Gorman, Matthew F Krummel, Annemieke van Zante, Alexis J Combes, Michael Angelo, Lawrence Fong, Alain P Algazi, Patrick Ha, Matthew H Spitzer.

  CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LNs, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8+ T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the tumor. After anti-PD-L1 immunotherapy, Tpex in uninvolved LNs reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8+ T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LNs, these response hallmarks were impaired, with immunosuppressive cellular niches. Our results identify important roles for LNs in anti-tumor immune responses in humans.

Keywords:  CD8(+) T cells; T cell exhaustion; cancer immunotherapy; immune checkpoint blockade; lymph nodes

DOI:  https://doi.org/10.1016/j.cell.2023.02.021