263 Pleiotropic effects of IL-7 in prostate cancer patients receiving Sipuleucel-T vaccination

BackgroundSipuleucel-T (Provenge) is the first therapeutic vaccination approved by the FDA so far, indicated for advanced metastatic prostate cancer patients. Despite an improvement of the overall survival, the benefits of the therapy are still short-term so increasing the duration of the efficacy is necessary. Specifically, T-cell anergy is one of the challenges that we need to overcome to improve the overall efficacy. IL-7 is known to promote the naive T cell activation and to increase the proliferation and activation of the T cell memory subsets. Therefore, in this phase II clinical trial, we tested the therapeutic potential of a human recombinant glycosylated IL-7 after completion of the Provenge therapy on asymptomatic advanced prostate cancer patients.MethodsTo get a comprehensive analysis of the immune landscape in these patients, we performed CyTOF analysis on PBMC samples obtained at week 1 (baseline) and week 6 after the beginning of the IL-7 therapy. After stimulation with PMA/Ionomycin, we proceeded to surface and intracellular cytokine staining before acquisition on the CyTOF. The data were then analyzed by expert gating on Cytobank.ResultsAt 6 weeks post therapy, our data showed an increase in the number of circulating T lymphocytes in the IL-7 cohort, especially CD8 T cells, in accordance with previous literature. Even though of the frequency of CD4 T cells did not increase, the cells showed greater functionalities, with increased expression of IL-2, TNFα and IL-6 upon stimulation by PMA-Ionomycine. Cytotoxic subsets were also positively affected, with increased expression of IFNγ in CD8 T cells, TNFα in NK cells and IL-2 in γδ T cells. Moreover, PD-1 expression was decreased on CD4, CD8 and γδ T cells while CD137 increased on CD4, CD8 and NK cells. In addition, despite a reduction in the pool of circulating monocytes, we observed higher TNFα expression in these cells.ConclusionsAltogether, our data revealed multiple effects of IL-7 in these patients, highlighting a complex set of in vivo mechanisms. In the future, knowledge of these effects may help in choosing the best agents to use in combination with IL-7 and/or the best patients to benefit from IL-7 as part of their therapeutic approach.Trial RegistrationNCT01881867Ethics ApprovalThe study was last approved by Fred Hutchinson Cancer Research Center Institutional Review Board, IR file 8037, on January 23, 2020

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Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽

10.1182/blood-2010-03-275438 ◽

2010 ◽

Vol 116 (17) ◽

pp. 3238-3248 ◽

Cited By ~ 72

Author(s):

Enrico Lugli ◽

Carolyn K. Goldman ◽

Liyanage P. Perera ◽

Jeremy Smedley ◽

Rhonda Pung ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Nk Cell ◽

The Body ◽

Effector Memory ◽

Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

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New Insights into the Mechanism of Action (MoA) of First-in-Class IgG-Based Bcma T-Cell Bispecific Antibody (TCB) for the Treatment of Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v128.22.2096.2096 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2096-2096 ◽

Cited By ~ 7

Author(s):

Laura Moreno ◽

Aintzane Zabaleta ◽

Diego Alignani ◽

Marta Lasa ◽

Patricia Maiso ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

T Cell Activation ◽

Cd8 T Cells ◽

Research Funding ◽

Cell Activation ◽

Rational Combination ◽

Dose Dependent ◽

Tumor Cell Lysis

Abstract Novel agents have improved outcomes in MM, but prognosis after patients relapse remains poor and new drugs with novel MoA are needed. The breakthrough of immuno-oncology has rendered new therapeutic options, and most recently we reported on EM801, a novel BCMA-TCB that showed remarkably efficacy when used as single agent in primary bone marrow (BM) samples from MM patients (Seckinger, Blood 2015;126: abstr 117). Because of its novelty, further knowledge about the MoA of BCMA-TCB is of utmost importance to improve its efficacy by designing rational treatment combinations. In order to optimize the in vitro efficacy of the BCMA-TCB, we started by investigating in primary BM samples from 6 MM patients whether longer treatment periods with BCMA-TCB2 (a BCMA-TCB candidate sharing similar "2+1" structure of EM801 but displaying higher affinity to BCMA) would increase MM cell death. Upon treating samples with BCMA-TCB2 for 48h vs 96h, we noted a 2-fold increment in MM tumor cell lysis at 1nM and 10nM concentrations (Panel A). In parallel, the phenotypic profiles of CD4 and CD8 T cells showed that BCMA-TCB2 induced robust activation (ie. dose-dependent increment in CD69, CD25, HLADR after exposure to 100pM, 1nM and 10nM of BCMA-TCB2), but also led to the natural emergence of the checkpoint inhibitor PD-1 in the surface of activated CD4 and CD8 T cells (Panel B). We then investigated if there was a correlation between the percentage of PD-1 positive CD4 and CD8 T cells and the efficacy of BCMA-TCB2; interestingly, those patients with lower frequencies of PD-1 positive CD4 and CD8 T cells prior to treatment showed the highest rates of MM tumor cell lysis after 48h and 96h of BCMA-TCB2 at 10nM of (r=0.6, P=0.04; Panel C). By contrast, upon measuring the concentration of soluble BCMA and APRIL in the supernatants of primary BM samples from 16 MM patients treated with BCMA-TCB, we found no significant differences between responding (n=11) and non-responding (n=5) patients. Similar results were observed upon comparing the density of BCMA in the surface of MM tumor cells from responding vs non-responding patients (1256 vs 1522 SABC units; P=87). Since the efficacy of BCMA-TCB2 was found to be intrinsically related to the phenotype and activation status of T cells, we then investigated whether we could further harness immune cells by combining BCMA-TCB2 with three drugs representing different types of immunotherapy: lenalidomide (IMIDs), anti-PD1 (checkpoint inhibitors) and daratumumab (mAb). H929 MM cells were co-cultured with human leukocytes (n=5) and challenged to suboptimal concentrations of BCMA-TCB2 (10pM) alone, or in combination with standard doses of lenalidomide (1µM), anti-PD1 (10µg/ml) and daratumumab (10µg/ml) (Panel D). Interestingly, we observed that combining BCMA-TCB2 with lenalidomide or daratumumab significantly increased their anti-MM efficacy by 4-fold and 2.5-fold, respectively. Because lenalidomide and daratumumab share in common that they rely, at least in part, on activated NK cells to eradicate MM cells, we hypothesized whether such robust T cell activation induced by BCMA-TCB2 was leading to co-stimulation of NK cells. First, we demonstrated by analyzing the transcriptomes of T cells prior and after treatment exposure (n=3), that BCMA-TCB2 modulated the transcriptomes of CD4 and CD8 T cells (159 and 141 deregulated genes, respectively), consistent with enhanced activation and T-cell mediated inflammatory response (eg. TNFRS18, STAT1, CCL4). Furthermore, we observed a dose-dependent and significant increment of the CD69 (2-fold), CD25 (2.5-fold) and HLADR (4-fold) activation markers in the surface of NK cells from primary BM samples of 11 MM patients treated with BCMA-TCB2 (Panel E), suggesting a functional crosstalk between activated T cells and NK cells. In conclusion, we showed that the promising pre-clinical activity of the first-in-class IgG-based BCMA-TCB can be further enhanced by longer treatment periods followed by robust T cell activation. The observation that the efficacy of BCMA-TCB is intrinsically related to the activation status of T cells suggests its rational combination with IMIDs as demonstrated here. Most interestingly, potential crosstalk between activated T and NK cells could lead to enhanced function of the later immune subset, and provide a rational combination between BCMA-TCB and anti-CD38 antibodies to eradicate MM cells through highly activated T and NK cells. Figure Figure. Disclosures Strein: EngMab: Employment. Vu:EngMab: Employment. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

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Deoxynivalenol Affects Proliferation and Expression of Activation-Related Molecules in Major Porcine T-Cell Subsets

Toxins ◽

10.3390/toxins11110644 ◽

2019 ◽

Vol 11 (11) ◽

pp. 644 ◽

Cited By ~ 2

Author(s):

Vatzia ◽

Pierron ◽

Saalmüller ◽

Mayer ◽

Gerner

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Activation ◽

Mononuclear Cells ◽

Animal Feed ◽

Γδ T Cells ◽

T Cell Subsets ◽

Peripheral Blood Mononuclear

The Fusarium mycotoxin deoxynivalenol (DON) contaminates animal feed worldwide. In vivo, DON modifies the cellular protein synthesis, thereby also affecting the immune system. However, the functional consequences of this are still ill-defined. In this study, peripheral blood mononuclear cells from healthy pigs were incubated with different DON concentrations in the presence of Concanavalin A (ConA), a plant-derived polyclonal T-cell stimulant. T-cell subsets were investigated for proliferation and expression of CD8α, CD27, and CD28, which are involved in activation and costimulation of porcine T cells. A clear decrease in proliferation of all ConA-stimulated major T-cell subsets (CD4+, CD8+, and γδ T cells) was observed in DON concentrations higher than 0.4 µM. This applied in particular to naïve CD4+ and CD8+ T cells. From 0.8 μM onwards, DON induced a reduction of CD8α (CD4+) and CD27 expression (CD4+ and CD8+ T cells). CD28 expression was diminished in CD4+ and CD8+ T cells at a concentration of 1.6 µM DON. None of these effects were observed with the DON-derivative deepoxy-deoxynivalenol (DOM-1) at 16 µM. These results indicate that DON reduces T-cell proliferation and the expression of molecules involved in T-cell activation, providing a molecular basis for some of the described immunosuppressive effects of DON.

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Immune Cell Phenotype and Function After Treatment With Blinatumomab For Childhood Relapsed B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL)

Blood ◽

10.1182/blood.v122.21.2668.2668 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2668-2668 ◽

Cited By ~ 4

Author(s):

Alice Bertaina ◽

Perla Filippini ◽

Valentina Bertaina ◽

Barbarella Lucarelli ◽

Aurelie Bauquet ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Lymphoblastic Leukemia ◽

Γδ T Cells ◽

Cell Phenotype ◽

Ifn Γ

Abstract Background Blinatumomab is a bi-specific monoclonal antibody designed to engage and tether cytotoxic T-cells (CTL) to CD19-expressing target B cells. An ongoing phase I multicenter study in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has shown that blinatumomab induces morphological and molecular remissions, defined as minimal residual disease (MRD) levels <10-4, in 47% of patients [Gore L, et al. J Clin Oncol 31, 2013 (suppl; abstr 10007)]. It is presently unknown whether and to what extent blinatumomab affects T-cell phenotype and function in pediatric patients with BCP-ALL. Patients and Methods Eight children diagnosed with relapsed/refractory BCP-ALL at the Bambino Gesù Children’s Hospital in Rome (median age at diagnosis 5.8 years, range 0.5-14.6) received blinatumomab as continuous intravenous infusion for 28 consecutive days, followed by a 2-week drug-free period. Four out of 8 patients were given repeated treatment courses. Peripheral blood samples were collected before treatment (day 0) and weekly thereafter, for 4 consecutive weeks. Bone marrow (BM) aspirates were available on days 0 and +29 of each drug course. Peripheral blood mononuclear cells (PBMC) were labeled with appropriate combinations of fluorochrome-conjugated monoclonal antibodies to quantitate naïve/memory T cells, αβ/γδ-expressing T cells and other immune effectors with potential anti-leukemia activity, such as CD3+CD56+ natural killer (NK) T cells and CD3-CD56+ NK cells. T-cell production of interferon (IFN)-γ, interleukin (IL)-4 and IL-17 was measured at the single-cell level, after short-term (4-hour) stimulation with phorbol myristate acetate (PMA) and ionomycin. The TCR-Vβ Repertoire Kit® (Beckman Coulter, Milan, Italy) allowed the flow cytometry analysis of 24 different Vβ specificities on T cells, thus covering approximately 70% of the normal human TCR-Vβ repertoire. Results Peripheral blood lymphocytes reached their nadir on day +1 (median 300/µL of blood [inter-quartile range 40-380] compared with 1,080/µL of blood at baseline [inter-quartile range 360-2,310]; p=0.0037 by Mann-Whitney U test for paired data), expanded within 7 days up to 3.5-fold above baseline, and included both CD4+ and CD8+ T cells. By contrast, the frequency of both CD3+CD56+ NK T cells and CD3-CD56+ NK cells remained unchanged compared to baseline. IFN-γ production by patient-derived CD4+ T cells exceeded that observed in CD4+ T cells from healthy controls by 2-fold, indicating robust T helper type 1 (Th1) polarization. The frequency of Th2/Th17 cells, defined as CD4+IL-4+ and CD4+IL-17+ cells, respectively, was not different after treatment compared to baseline. CD31 expression on recovering CD45RA+ naïve T cells, a surrogate phenotypic feature for recent thymic emigrants (RTEs), suggested that thymic output may contribute to T-cell expansion after blinatumomab administration. Non-significant changes in the relative proportion of TCR-αβ and TCR-γδ-expressing CD3+ T cells were detected after treatment (median 79.5% TCR-αβ+ T cells and 19.3% TCR-γδ+ T cells among total CD3+ cells) compared with baseline (median 87.4% TCR-αβ+ T cells and 12.2% TCR-γδ+ T cells among total CD3+ cells). Importantly, both CD3+CD8bright T cells and NK cells expressed lytic granule proteins, such as perforin and granzyme-B, at levels that increased during treatment. The analysis of Vβ TCR repertoire revealed a restricted usage of single Vβ domains by BM-resident CD8+ T cells, but not by CD4+ T cells. Specifically, the sum of Vβ within CD8+ T cells in the BM averaged 56.7±6.2% after blinatumomab, compared with 78±5.1% in healthy controls (p=0.04; Mann-Whitney U test for unpaired data). Conclusions Blinatumomab expands both CD31+CD45RA+ thymic-naïve and memory T cells with heightened IFN-γ production and is highly effective at clearing MRD in children with BCP-ALL. Skewing of the Vβ repertoire within BM-resident CD8+ T cells may be consistent with clonal expansions. Disclosures: Zugmaier: Amgen: Employment.

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658 CD8 T cell activation in cancer is comprised of two distinct phases

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.658 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A686-A686

Author(s):

Nataliya Prokhnevska ◽

Maria Cardenas ◽

Rajesh Valanparambil ◽

Ewelina Sobierajska ◽

Caroline Jansen ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Cell Biology ◽

Cell Activation ◽

Cd8 T Cell ◽

Human Patient

BackgroundCD8 T cell are a crucial part of the immune response to tumors, with CD8 infiltration predicting disease progression in numerous cancer types. Recently two subsets of CD8 T cells that respond to tumors have been described, a stem-like (TCF1+) CD8 T cell that can give rise to a more cytotoxic terminally differentiated (TD) (TCF1-Tim3+) CD8 T cell. In this study we aimed to understand the origin of stem-like TCF1+ CD8 T cells within tumors.MethodsHuman patient TDLN and tumor samples from kidney and prostate cancer were processed after resection and used for flow cytometry, RNA-seq, TCR-seq and whole genome DNA methylation analysis. We also used a prostate cancer mouse model that expresses the LCMV GP protein (TRAMPC1-LCMV-GP) to track tumor-specific CD8 T cells in both TDLNs and tumors.ResultsWe studied human prostate and kidney cancer tumor-draining lymph nodes (TDLN) and found that CD8 T cells are activated but fail to acquire an effector phenotype within the TDLN. Instead, they share functional, transcriptional, and epigenetic traits with stem-like cells in the tumor. We also found that activated CD8 T cells from TDLNs shared TCR overlap with both CD8 subsets within tumors. This suggests that these activated cells are a precursor to the stem-like CD8 T cells in tumors. To further test this hypothesis, we used our TRAMPC1-LCMV-GP tumor model to study tumor-specific CD8 T cell activation. We found that CD8 T cells are activated in TDLNs but fail to acquire an effector program. These cells then establish the stem-like CD8s within tumor where they require additional co-stimulation from antigen presenting cells to differentiate into TCF1- TD CD8 T cells. This is strikingly different from canonical CD8 T cell activation to acute viruses, where the effector program is acquired immediately. We also showed that human stem-like CD8 T cells require co-stimulation and TCR stimulation to divide and differentiate into terminally differentiated CD8s in-vitro, and DCs from autologous tumors can also induce this differentiation.ConclusionsOverall this work shows a model of CD8 T cell activation in response to tumors that has two distinct phases. The first occurs in the TDLN where CD8 T cells are initially activated, the second occurs in the tumor where CD8 T cells acquire an effector function after additional co-stimulation. This model of T cell differentiation adds to our understanding of basic CD8 T cell biology and has important implications to improve our current immunotherapies.

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Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

Science Immunology ◽

10.1126/sciimmunol.abf7570 ◽

2021 ◽

Vol 6 (57) ◽

pp. eabf7570

Author(s):

Laura A. Vella ◽

Josephine R. Giles ◽

Amy E. Baxter ◽

Derek A. Oldridge ◽

Caroline Diorio ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

Immune Activation ◽

Cell Activation ◽

Vascular Complications ◽

Adult Disease ◽

Vasoactive Medication ◽

Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

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CD122-directed interleukin-2 treatment mechanisms in bladder cancer differ from αPD-L1 and include tissue-selective γδ T cell activation

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002051 ◽

2021 ◽

Vol 9 (4) ◽

pp. e002051

Author(s):

Ryan Michael Reyes ◽

Yilun Deng ◽

Deyi Zhang ◽

Niannian Ji ◽

Neelam Mukherjee ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Combination Treatment ◽

Treatment Efficacy ◽

Interleukin 2 ◽

Γδ T Cells ◽

T Cell Subsets ◽

Γδ T Cell

BackgroundAnti-programmed death-ligand 1 (αPD-L1) immunotherapy is approved to treat bladder cancer (BC) but is effective in <30% of patients. Interleukin (IL)-2/αIL-2 complexes (IL-2c) that preferentially target IL-2 receptor β (CD122) augment CD8+ antitumor T cells known to improve αPD-L1 efficacy. We hypothesized that the tumor microenvironment, including local immune cells in primary versus metastatic BC, differentially affects immunotherapy responses and that IL-2c effects could differ from, and thus complement αPD-L1.MethodsWe studied mechanisms of IL-2c and αPD-L1 efficacy using PD-L1+ mouse BC cell lines MB49 and MBT-2 in orthotopic (bladder) and metastatic (lung) sites.ResultsIL-2c reduced orthotopic tumor burden and extended survival in MB49 and MBT-2 BC models, similar to αPD-L1. Using antibody-mediated cell depletions and genetically T cell-deficient mice, we unexpectedly found that CD8+ T cells were not necessary for IL-2c efficacy against tumors in bladder, whereas γδ T cells, not reported to contribute to αPD-L1 efficacy, were indispensable for IL-2c efficacy there. αPD-L1 responsiveness in bladder required conventional T cells as expected, but not γδ T cells, altogether defining distinct mechanisms for IL-2c and αPD-L1 efficacy. γδ T cells did not improve IL-2c treatment of subcutaneously challenged BC or orthotopic (peritoneal) ovarian cancer, consistent with tissue-specific and/or tumor-specific γδ T cell contributions to IL-2c efficacy. IL-2c significantly altered bladder intratumoral γδ T cell content, activation status, and specific γδ T cell subsets with antitumor or protumor effector functions. Neither IL-2c nor αPD-L1 alone treated lung metastatic MB49 or MBT-2 BC, but their combination improved survival in both models. Combination treatment efficacy in lungs required CD8+ T cells but not γδ T cells.ConclusionsMechanistic insights into differential IL-2c and αPD-L1 treatment and tissue-dependent effects could help develop rational combination treatment strategies to improve treatment efficacy in distinct cancers. These studies also provide insights into γδ T cell contributions to immunotherapy in bladder and engagement of adaptive immunity by IL-2c plus αPD-L1 to treat refractory lung metastases.

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Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Nature ◽

10.1038/s41586-021-03752-4 ◽

2021 ◽

Author(s):

Justina X. Caushi ◽

Jiajia Zhang ◽

Zhicheng Ji ◽

Ajay Vaghasia ◽

Boyang Zhang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Single Cell ◽

T Cell Activation ◽

Cd8 T Cells ◽

T Cell Receptors ◽

Tumour Microenvironment ◽

Lung Cancers ◽

Cell Receptors ◽

Interleukin 7

AbstractPD-1 blockade unleashes CD8 T cells1, including those specific for mutation-associated neoantigens (MANA), but factors in the tumour microenvironment can inhibit these T cell responses. Single-cell transcriptomics have revealed global T cell dysfunction programs in tumour-infiltrating lymphocytes (TIL). However, the majority of TIL do not recognize tumour antigens2, and little is known about transcriptional programs of MANA-specific TIL. Here, we identify MANA-specific T cell clones using the MANA functional expansion of specific T cells assay3 in neoadjuvant anti-PD-1-treated non-small cell lung cancers (NSCLC). We use their T cell receptors as a ‘barcode’ to track and analyse their transcriptional programs in the tumour microenvironment using coupled single-cell RNA sequencing and T cell receptor sequencing. We find both MANA- and virus-specific clones in TIL, regardless of response, and MANA-, influenza- and Epstein–Barr virus-specific TIL each have unique transcriptional programs. Despite exposure to cognate antigen, MANA-specific TIL express an incompletely activated cytolytic program. MANA-specific CD8 T cells have hallmark transcriptional programs of tissue-resident memory (TRM) cells, but low levels of interleukin-7 receptor (IL-7R) and are functionally less responsive to interleukin-7 (IL-7) compared with influenza-specific TRM cells. Compared with those from responding tumours, MANA-specific clones from non-responding tumours express T cell receptors with markedly lower ligand-dependent signalling, are largely confined to HOBIThigh TRM subsets, and coordinately upregulate checkpoints, killer inhibitory receptors and inhibitors of T cell activation. These findings provide important insights for overcoming resistance to PD-1 blockade.

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Regulation and Functions of Protumoral Unconventional T Cells in Solid Tumors

Cancers ◽

10.3390/cancers13143578 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3578

Author(s):

Emilie Barsac ◽

Carolina de Amat Herbozo ◽

Loïc Gonzalez ◽

Thomas Baranek ◽

Thierry Mallevaey ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Immunity ◽

Cell Biology ◽

Therapeutic Potential ◽

Γδ T Cells ◽

Feasibility Studies ◽

T Cell Subsets ◽

Mait Cells ◽

Nonpeptide Antigens

The vast majority of studies on T cell biology in tumor immunity have focused on peptide-reactive conventional T cells that are restricted to polymorphic major histocompatibility complex molecules. However, emerging evidence indicated that unconventional T cells, including γδ T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells are also involved in tumor immunity. Unconventional T cells span the innate–adaptive continuum and possess the unique ability to rapidly react to nonpeptide antigens via their conserved T cell receptors (TCRs) and/or to activating cytokines to orchestrate many aspects of the immune response. Since unconventional T cell lineages comprise discrete functional subsets, they can mediate both anti- and protumoral activities. Here, we review the current understanding of the functions and regulatory mechanisms of protumoral unconventional T cell subsets in the tumor environment. We also discuss the therapeutic potential of these deleterious subsets in solid cancers and why further feasibility studies are warranted.

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