Immuno-transcriptomic profiling of blood and tumor tissue identifies gene signatures associated with immunotherapy response in metastatic bladder cancer

<p>The dataset contains RNA-sequencing data (raw fastq files, not trimmed) of whole blood and whole bladder tissue samples and metadata file with sample annotation. The samples have been collected in the context of the study "Immuno-transcriptomic profiling of blood and tumor tissue identifies gene signatures associated with immunotherapy response in metastatic bladder cancer". In this study, we investigated which are the local and systemic immune changes in an experimental model of muscle-invasive bladder cancer upon immunotherapy. The RNA-sequencing data have been used to produce the results presented in the study. Please refer to the study publication material and methods and the metadata file for details.</p&gt

From T cell “exhaustion” to anti-cancer immunity

The immune system has the potential to protect from malignant diseases for extended periods of time. Unfortunately, spontaneous immune responses are often inefficient. Significant effort is required to develop reliable, broadly applicable immunotherapies for cancer patients. A major innovation was transplantation with hematopoietic stem cells from genetically distinct donors for patients with hematologic malignancies. In this setting, donor T cells induce long-term remission by keeping cancer cells in check through powerful allogeneic graft-versus-leukemia effects. More recently, a long awaited breakthrough for patients with solid tissue cancers was achieved, by means of therapeutic blockade of T cell inhibitory receptors. In untreated cancer patients, T cells are dysfunctional and remain in a state of T cell "exhaustion". Nonetheless, they often retain a high potential for successful defense against cancer, indicating that many T cells are not entirely and irreversibly exhausted but can be mobilized to become highly functional. Novel antibody therapies that block inhibitory receptors can lead to strong activation of anti-tumor T cells, mediating clinically significant anti-cancer immunity for many years. Here we review these new treatments and the current knowledge on tumor antigen-specific T cells

Temporal cross-talk between TCR and STAT signals for CD8 T cell effector differentiation.

The strength and duration of signaling through surface receptors is a primary means of controlling cell fate decisions. In adaptive immunity, Ag-initiated T cell stimulation is secondarily regulated by cytokines. We here summarize evidence for temporal control of a gene expression program in naive CD8 T cells. It is initiated in response to TCR engagement but relies on secondary signaling from cytokine receptors to be sustained and to allow development of full effector capacity. This mechanism permits cytokine receptor signaling to rescue abortive TCR signaling, such as that induced in response to weak or partial TCR agonists. Indeed, limiting TCR-initiated signaling on the Ras/ERK pathway may be complemented by STAT activation. Thus, TCR- and cytokine-driven activation of transcription factors and epigenetic modifications may act in concert in a temporally staggered process to establish the functional program of effector CD8 T cells. Based on gene expression profiling, molecular targets whose activation or inactivation may boost or dampen CD8 T cell effectors are also identified. Manipulation of these targets may, respectively, increase anti-tumor responses or prevent graft-versus-host reactions

STAT5-mediated signals sustain a TCR-initiated gene expression program toward differentiation of CD8 T cell effectors.

Poorly functional effector CD8 T cells are generated in some pathological situations, including responses to weakly antigenic tumors. To identify the molecular bases for such defective differentiation, we monitored gene expression in naive monoclonal CD8 T cells during responses to TCR ligands of different affinity. We further evaluated whether responses to weak Ags may be improved by addition of cytokines. Transient gene expression was observed for a cluster of genes in response to the weak TCR agonist. Strikingly, gene expression was stabilized by low dose IL-2. This IL-2-sustained gene cluster encoded notably transcripts for CD25, cytolytic effector molecules (granzyme B) and TNF-R family costimulatory molecules (glucocorticoid-induced TNF-R (GITR), OX40, and 4-1BB). IL-2-enhanced surface expression or function was also demonstrated in vivo for these genes. A constitutive active form of STAT5 mimicked the IL-2 effect by sustaining transcripts for the same gene cluster. Consistent with this, under conditions of low avidity TCR engagement and IL-2 treatment, endogenous STAT5 binding to 4-1BB and granzyme B promoters was demonstrated by chromatin immunoprecipitation. This study highlights those genes for which IL-2, via STAT5 activation, acts as a stabilizer of gene regulation initiated by TCR signals, contributing to the development of a complete CD8 T cell effector program

Bases moléculaires de l'hétérogénéité fonctionnelle des lymphocytes T CD8

Les lymphocytes T CD8 sont impliqués dans le contrôle de phénomènes néoplasiques, ainsi que dans les réactions contre des transplants allogéniques. Dans des conditions optimales de stimulations, on observe une prolifération clonale, une différentiation complète en effecteur cytolytique (CTL) et en cellules T mémoires. Cependant de nombreuses situations pathologiques ne fournissent qu'un contexte de stimulation sub-optimale conduisant à l'émergence de cellules T partiellement fonctionnelles. Afin de mettre en évidence les bases moléculaires menant à l'hétérogénéité fonctionnelle des cellules T CD8+, nous avons, dans un modèle d'alloréactivité, analysé une cinétique des profils d'expression génique induits dans une population T CD8 naïve par deux types d'agonistes de forte ou faible avidité. Nous avons ainsi mis en évidence un profil d'expression transitoire en réponse à un agoniste partiel qui peut, pour certains gènes, être stabilisé par l'ajout d'IL-2. Parmi ces gènes ont trouve les membres de la superfamille des récepteurs au TNF 4-1BB, GITR et OX40. Une forme constitutivement active de STAT5 reproduit l'effet obtenu en présence d'IL-2. Ce travail montre que l'IL-2 est aussi un facteur de différenciation important pour l'acquisition des fonctions effectrices des cellules CD8 naïves et n'agit pas comme facteur de croissance à ce stade. Afin de voir si, comme le suggère certaines études, l'environnement tumoral peut modifier le programme d'expression génique des lymphocytes infiltrant une tumeur, nous avons comparé les transcriptomes de cellules T CD8 spécifiques d'un antigène tumoral et de cellules NK, issues de ganglions ou d'une tumeur solide. Cette étude met en évidence une activation des cellules NK seulement en présence de cellules T CD8 activées et montre que la réponse immunitaire adaptative peut recruter et activer ocalement les effecteurs anti-tumoraux innés.Although NK cells and CD8 T cells have both been shown capable of anti-tumor responses, RAG-deficient mice, which have a normal component of NK cells, are incapable of rejecting the P815 mastocytoma tumor. We established a model where CD8 T cell reactivity was restricted to a single epitope of the tumor Ag P1A expressed on the P815 mastocytoma. Reconstitution of the RAG-deficient mice with monoclonal naïve CD8 T cells with a TCR specific for P1A (TCRP1A) afforded efficient resistance to tumor growth selectively for the P1A-expressing, and not for a P1A-negative variant of P815. Nevertheless, P1A specific CD8 T cells were efficient at promoting the NK cell dependent rejection of the P1A-negative tumors when both P1A-positive and -negative tumors were present at the same site. Gene expression profiling in NK cells infiltrating the P1A-positive as compared to the P1Anegative tumor in mice transferred with P1A-reactive CD8 T cells established their acquisition of an activated effector phenotype. The help from CD8 T cells was provided locally because it did not induce the rejection of a P1A-negative variant, nor the activation of NK cells at a distant site. These results illustrate a mechanism by which, in the face of immunoselection / editing, thesynergy between specific anti-tumor Ag T cell responses and natural effectors can contribute to the elimination of tumor cells whether or not they express the T cell tumor Ag epitope. This mechanism appears ineffective, however, once tumor variants lacking a T cell-recognized epitope are separated from the wild-type tumor, as would be the case in tumor metastasis.AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF