Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

Differential requirements for CD4+ T cells in the efficacy of the anti-PD-1+LAG-3 and anti-PD-1+CTLA-4 combinations in melanoma flank and brain metastasis models.

BACKGROUND: Although the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combinations are effective in advanced melanoma, it remains unclear whether their mechanisms of action overlap. METHODS: We used single cell (sc) RNA-seq, flow cytometry and IHC analysis of responding SM1, D4M-UV2 and B16 melanoma flank tumors and SM1 brain metastases to explore the mechanism of action of the anti-PD-1+LAG-3 and the anti-PD-1+CTLA-4 combination. CD4+ and CD8+ T cell depletion, tetramer binding assays and ELISPOT assays were used to demonstrate the unique role of CD4+T cell help in the antitumor effects of the anti-PD-1+LAG-3 combination. RESULTS: The anti-PD-1+CTLA-4 combination was associated with the infiltration of FOXP3+regulatory CD4+ cells (Tregs), fewer activated CD4+T cells and the accumulation of a subset of IFNγ secreting cytotoxic CD8+T cells, whereas the anti-PD-1+LAG-3 combination led to the accumulation of CD4+T helper cells that expressed CXCR4, TNFSF8, IL21R and a subset of CD8+T cells with reduced expression of cytotoxic markers. T cell depletion studies showed a requirement for CD4+T cells for the anti-PD-1+LAG-3 combination, but not the PD-1-CTLA-4 combination at both flank and brain tumor sites. In anti-PD-1+LAG-3 treated tumors, CD4+T cell depletion was associated with fewer activated (CD69+) CD8+T cells and impaired IFNγ release but, conversely, increased numbers of activated CD8+T cells and IFNγ release in anti-PD-1+CTLA-4 treated tumors. CONCLUSIONS: Together these studies suggest that these two clinically relevant immune checkpoint inhibitor (ICI) combinations have differential effects on CD4+T cell polarization, which in turn, impacted cytotoxic CD8+T cell function. Further insights into the mechanisms of action/resistance of these clinically-relevant ICI combinations will allow therapy to be further personalized.

Targeting intracellular oncoproteins with dimeric IgA promotes expulsion from the cytoplasm and immune-mediated control of epithelial cancers.

Dimeric IgA (dIgA) can move through cells via the IgA/IgM polymeric immunoglobulin receptor (PIGR), which is expressed mainly on mucosal epithelia. Here, we studied the ability of dIgA to target commonly mutated cytoplasmic oncodrivers. Mutation-specific dIgA, but not IgG, neutralized KRASG12D within ovarian carcinoma cells and expelled this oncodriver from tumor cells. dIgA binding changed endosomal trafficking of KRASG12D from accumulation in recycling endosomes to aggregation in the early/late endosomes through which dIgA transcytoses. dIgA targeting of KRASG12D abrogated tumor cell proliferation in cell culture assays. In vivo, KRASG12D-specific dIgA1 limited the growth of KRASG12D-mutated ovarian and lung carcinomas in a manner dependent on CD8+ T cells. dIgA specific for IDH1R132H reduced colon cancer growth, demonstrating effective targeting of a cytoplasmic oncodriver not associated with surface receptors. dIgA targeting of KRASG12D restricted tumor growth more effectively than small-molecule KRASG12D inhibitors, supporting the potential of this approach for the treatment of human cancers.

Enniatin A inhibits the chaperone Hsp90 and unleashes the immune system against triple-negative breast cancer.

Low response rates and immune-related adverse events limit the remarkable impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) and less than optimal dosing of these inhibitors limited their clinical efficacy as monotherapies. We discovered that the natural product Enniatin A (EnnA) targets Hsp90 and destabilizes its client oncoproteins without inducing an HSR. EnnA triggers immunogenic cell death in triple-negative breast cancer (TNBC) syngeneic mouse models and exhibits superior antitumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment (TME) to promote CD8+ T cell-dependent antitumor immunity by reducing PD-L1 levels and activating the chemokine receptor CX3CR1 pathway. These findings provide strong evidence for transforming the immunosuppressive TME into a more tumor-hostile milieu by engaging Hsp90 with therapeutic agents involving novel mechanisms of action.

Relationships among Inflammatory Biomarkers and Objectively Assessed Physical Activity and Sleep during and after Chemotherapy for Gynecologic Malignancies.

Little is known regarding associations between inflammatory biomarkers and objectively measured physical activity and sleep during and after chemotherapy for gynecologic cancer; thus, we conducted a longitudinal study to address this gap. Women with gynecologic cancer (patients) and non-cancer controls (controls) completed assessments before chemotherapy cycles 1, 3, and 6 (controls assessed contemporaneously), as well as at 6- and 12-month follow-ups. Physical activity and sleep were measured using wrist-worn actigraphs and sleep diaries, and blood was drawn to quantify circulating levels of inflammatory markers. Linear and quadratic random-effects mixed models and random-effects fluctuation mixed models were used to examine physical activity and sleep over time, as well as the associations with inflammatory biomarkers. On average, patients (n = 97) and controls (n = 104) were 62 and 58 years old, respectively. Compared to controls, patients were less active, more sedentary, had more time awake after sleep onset, and had lower sleep efficiency (p-values < 0.05). Across groups, higher levels of TNF-α were associated with more sedentary time and less efficient sleep (p-values ≤ 0.05). Higher levels of IL-1ß, TNF-α, and IL-6 were associated with lower levels of light physical activity (p-values < 0.05). Associations between inflammatory biomarkers, physical activity, and sleep did not differ between patients and controls. Given these results, we speculate that inflammation may contribute to less physical activity and more sleep problems that persist even 12 months after completing chemotherapy.

Relationships among Inflammatory Biomarkers and Self-Reported Treatment-Related Symptoms in Patients Treated with Chemotherapy for Gynecologic Cancer: A Controlled Comparison.

Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients (n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls (n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep (ps < 0.05). Patients reported lower levels of baseline physical activity (p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity (ps < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity.

PATH-SURVEYOR: pathway level survival enquiry for immuno-oncology and drug repurposing.

Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.

DRPPM-PATH-SURVEIOR: Plug-and-Play Survival Analysis of Pathway-level Signatures and Immune Components.

Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, DRPPM-PATH-SURVEIOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis (GSEA) and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient's clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.

Neglected no more: B cell-mediated anti-tumor immunity.

Immuno-oncology has traditionally focused on the cellular arm of the adaptive immune response, while attributing tumor-promoting activity to humoral responses in tumor-bearing hosts. This view stems from mouse models that do not necessarily recapitulate the antibody response process consistently observed in most human cancers. In recent years, the field has reconsidered the coordinated action of T and B cell responses in the context of anti-tumor immunity, as in any other immune response. Thus, recent studies in human cancer identify B cell responses with better outcome, typically in association with superior T cell responses. An area of particular interest is tertiary lymphoid structures, where germinal centers produce isotype switched antibodies and B cells and T lymphocytes interact with other immune cell types. The presence of these lymphoid structures is associated with better immunotherapeutic responses and remain poorly understood. Here, we discuss recent discoveries on how coordination between humoral and cellular responses is required for effective immune pressure against malignant progression, providing a perspective on the role of tertiary lymphoid structures and interventions to elicit their formation in unresectable tumors.

Affinity-matured DLL4 ligands as broad-spectrum modulators of Notch signaling.

The Notch pathway regulates cell fate decisions and is an emerging target for regenerative and cancer therapies. Recombinant Notch ligands are attractive candidates for modulating Notch signaling; however, their intrinsically low receptor-binding affinity restricts their utility in biomedical applications. To overcome this limitation, we evolved variants of the ligand Delta-like 4 with enhanced affinity and cross-reactivity. A consensus variant with maximized binding affinity, DeltaMAX, binds human and murine Notch receptors with 500- to 1,000-fold increased affinity compared with wild-type human Delta-like 4. DeltaMAX also potently activates Notch in plate-bound, bead-bound and cellular formats. When administered as a soluble decoy, DeltaMAX inhibits Notch in reporter and neuronal differentiation assays, highlighting its dual utility as an agonist or antagonist. Finally, we demonstrate that DeltaMAX stimulates increased proliferation and expression of effector mediators in T cells. Taken together, our data define DeltaMAX as a versatile tool for broad-spectrum activation or inhibition of Notch signaling.

Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.

Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids1-3. During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8+ T cells4,5. Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8+ T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8+ T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8+ T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8+ T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.

Ablation of the endoplasmic reticulum stress kinase PERK induces paraptosis and type I interferon to promote anti-tumor T cell responses.

Activation of unfolded protein responses (UPRs) in cancer cells undergoing endoplasmic reticulum (ER) stress promotes survival. However, how UPR in tumor cells impacts anti-tumor immune responses remains poorly described. Here, we investigate the role of the UPR mediator pancreatic ER kinase (PKR)-like ER kinase (PERK) in cancer cells in the modulation of anti-tumor immunity. Deletion of PERK in cancer cells or pharmacological inhibition of PERK in melanoma-bearing mice incites robust activation of anti-tumor T cell immunity and attenuates tumor growth. PERK elimination in ER-stressed malignant cells triggers SEC61ß-induced paraptosis, thereby promoting immunogenic cell death (ICD) and systemic anti-tumor responses. ICD induction in PERK-ablated tumors stimulates type I interferon production in dendritic cells (DCs), which primes CCR2-dependent tumor trafficking of common-monocytic precursors and their intra-tumor commitment into monocytic-lineage inflammatory Ly6C+CD103+ DCs. These findings identify how tumor cell-derived PERK promotes immune evasion and highlight the potential of PERK-targeting therapies in cancer immunotherapy.

TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate.

Chronic T-cell receptor (TCR) signaling in the tumor microenvironment is known to promote T-cell dysfunction. However, we reasoned that poorly immunogenic tumors may also compromise T cells by impairing their metabolism. To address this, we assessed temporal changes in T-cell metabolism, fate, and function in models of B-cell lymphoma driven by Myc, a promoter of energetics and repressor of immunogenicity. Increases in lymphoma burden most significantly impaired CD4+ T-cell function and promoted regulatory T cell (Treg) and Th1-cell differentiation. Metabolomic analyses revealed early reprogramming of CD4+ T-cell metabolism, reduced glucose uptake, and impaired mitochondrial function, which preceded changes in T-cell fate. In contrast, B-cell lymphoma metabolism remained robust during tumor progression. Finally, mitochondrial functions were impaired in CD4+ and CD8+ T cells in lymphoma-transplanted OT-II and OT-I transgenic mice, respectively. These findings support a model, whereby early, TCR-independent, metabolic interactions with developing lymphomas limits T cell-mediated immune surveillance.

Perspectiva del cuidado en la ciberpsicología: reflexiones éticas / Care Approach to Cyberpsychology: Ethical Considerations / Perspectiva do cuidado em ciberpsicologia: reflexões éticas

Introducción. El despliegue de nuevas tecnologías de la información y la comunicación lleva a plantear la ciberpsicología como la integración de los medios digitales a la vida y las relaciones humanas, así como la inmersión tecnológica en la práctica profesional; esto implica retos en la comprensión de los cambios que ha producido la tecnología en el desarrollo individual y social. El objetivo del presente artículo fue plantear una reflexión sobre los aspectos éticos en la ciberpsicología y las implicaciones prácticas, a la luz de una perspectiva del cuidado que integra el principio del bienestar en un entorno virtual. Temas de reflexión. En primer lugar, se analizan las principales normativas en el marco de los principios éticos y bioéticos, con énfasis en el contexto colombiano. En segundo lugar, se reflexiona sobre la perspectiva del cuidado y algunas consideraciones en los medios digitales. Finalmente, se revisan algunas implicaciones prácticas de la ciberpsicología. Conclusiones. La perspectiva del cuidado y su aplicación en la ciberpsicología es uno de los anclajes éticos orientados a la promoción de relaciones basadas en el bienestar. Las discusiones éticas desde la perspectiva del cuidado en medios digitales integra la competencia técnico-profesional a la competencia ética. Esto implica un constante análisis de la apropiación de las tecnologías como espacio de encuentro y también como parte del compromiso con el cuidado propio y de los usuarios

Introduction. The spread of new information and communication technologies results in cyberpsychology being proposed as the integration of new digital media into human relationships and life, also, as technological immersion in professional practices. This implies challenges in understanding the changes that technology has produced in individual and social development. The objective of this article was to propose a reflection on the ethical aspects of cyberpsychology and its practical implications, according to a care approach which integrates the wellbeing principle in a virtual environment. Topics of reflection. Firstly, the main regulations for cyberpsychology are analyzed in the framework of the ethical and bioethical principles, with emphasis on the Colombian context. Secondly, we reflect on the care approach and some considerations for digital media. Finally, some practical implications of cyberpsychology are reviewed. Conclusions. The care approach and its application to cyberpsychology is one of the ethical anchors aimed at the promotion of wellbeing-based relationships. Ethical discussions from the care approach to digital media integrate technical-professional competency with ethical competency. This implies a constant analysis of the appropriation of technologies as a meeting space and as part of the commitment to self and user care.

Introdução. A implantação de novas tecnologias de informação e comunicação leva a postular a ciberpsicologia como a integração das mídias digitais na vida e nas relações humanas, bem como a imersão tecnológica na prática profissional. Isso implica desafios na compreensão das mudanças que a tecnología tem produzido no desenvolvimento individual e social. O objetivo deste artigo foi propor uma reflexão sobre os aspectos éticos na ciberpsicologia e as implicações práticas, à luz de uma perspectiva assistencial que integre o princípio do bem-estar no ambiente virtual. Tópicos de reflexão. Em primeiro lugar, analisamse as principais regulamentações no marco dos princípios éticos e bioéticos, com ênfase no contexto colombiano. Em segundo lugar, reflete-se sobre a perspectiva do cuidado e algumas considerações nos meios digitais. Finalmente, são revisadas algumas implicações práticas da ciberpsicologia. Conclusões. A perspectiva do cuidado e sua aplicação na ciberpsicologia é uma das âncoras éticas voltadas à promoção de relações baseadas no bem-estar. As discussões éticas na perspectiva do cuidado em mídia digital integram competência técnico-profissional com a competência ética. Isso implica uma análise constante da apropriação das tecnologias como espaço de encontro, assim como parte do compromisso com o autocuidado e dos usuários

Decoding endoplasmic reticulum stress signals in cancer cells and antitumor immunity.

The tumor microenvironment (TME) provokes endoplasmic reticulum (ER) stress in malignant cells and infiltrating immune populations. Sensing and responding to ER stress is coordinated by the unfolded protein response (UPR), an integrated signaling pathway governed by three ER stress sensors: activating transcription factor (ATF6), inositol-requiring enzyme 1α (IRE1α), and protein kinase R (PKR)-like ER kinase (PERK). Persistent UPR activation modulates malignant progression, tumor growth, metastasis, and protective antitumor immunity. Hence, therapies targeting ER stress signaling can be harnessed to elicit direct tumor killing and concomitant anticancer immunity. We highlight recent findings on the role of the ER stress responses in onco-immunology, with an emphasis on genetic vulnerabilities that render tumors highly sensitive to therapeutic UPR modulation.

Tumor-directed dysregulation of erythroid progenitors drives immunosuppressive myeloid cells.

In this issue of Cancer Cell, Long et al. demonstrate that tumors can reprogram erythroid progenitors into myeloid-erythroid cells that promote immunosuppression. Erythroid-differentiated myeloid cells (EDMCs) expand in cancer-bearing individuals, resemble the functionality of myeloid-derived suppressor cells (MDSCs), and correlate with poor response to immune-checkpoint inhibitors (ICIs) and tumor-related anemia.

Carbon Monoxide Activates PERK-Regulated Autophagy to Induce Immunometabolic Reprogramming and Boost Antitumor T-cell Function.

Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER-mitochondria cross-talk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test whether engaging moderate ERS conditions can improve mitochondrial and antitumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased antitumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong antitumor potential, whereas LC3-GFPneg cells exhibited a T regulatory-like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their antitumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells toward a superior antitumor phenotype to achieve robust tumor control. SIGNIFICANCE: Transient activation of ER stress with carbon monoxide drives mitochondrial biogenesis and protective autophagy that elicits superior antitumor T-cell function, revealing an approach to improving adoptive cell efficacy therapy.

Ovarian cancer immunogenicity is governed by a narrow subset of progenitor tissue-resident memory T cells.

Despite repeated associations between T cell infiltration and outcome, human ovarian cancer remains poorly responsive to immunotherapy. We report that the hallmarks of tumor recognition in ovarian cancer-infiltrating T cells are primarily restricted to tissue-resident memory (TRM) cells. Single-cell RNA/TCR/ATAC sequencing of 83,454 CD3+CD8+CD103+CD69+ TRM cells and immunohistochemistry of 122 high-grade serous ovarian cancers shows that only progenitor (TCF1low) tissue-resident T cells (TRMstem cells), but not recirculating TCF1+ T cells, predict ovarian cancer outcome. TRMstem cells arise from transitional recirculating T cells, which depends on antigen affinity/persistence, resulting in oligoclonal, trogocytic, effector lymphocytes that eventually become exhausted. Therefore, ovarian cancer is indeed an immunogenic disease, but that depends on ∼13% of CD8+ tumor-infiltrating T cells (∼3% of CD8+ clonotypes), which are primed against high-affinity antigens and maintain waves of effector TRM-like cells. Our results define the signature of relevant tumor-reactive T cells in human ovarian cancer, which could be applicable to other tumors with unideal mutational burden.