Physiological Regulation of Innate Lymphoid Cells

Discovery of innate lymphoid cells (ILCs) have provoked a paradigm shift in our understanding of the immune protection. Their constitutive presence and activity at the body's barrier surfaces ensure the maintenance of the tissue homeostasis and immune protection. This complex family has distinct and non-redundant functions that can have both beneficial and detrimental effects on disease outcome. The capacity of ILCs to perform their function effectively relies on their ability to sense and integrate intrinsic and extrinsic signals. Recent studies have shown that ILCs are not only sensitive to pathogen-derived stimuli but are also very well equipped to sense host-derived signals such as neuropeptides, hormones, and metabolites. The integration of these signals represents a complex and constant cross-talk between the immune system and the physiological systems of the body, including the nervous, endocrine, digestive, and reproductive systems. The physiological regulation of ILCs constitutes an important step in our understanding of the events leading to the protective and pathological properties of these cells. This review summarizes the recent advances in the understanding of the regulation of ILCs by physiological signals and their consequences on the maintenance of tissue homeostasis

Targeting Chemokines and Chemokine Receptors in Melanoma and Other Cancers

The tumor microenvironment is highly heterogeneous. It is composed of a diverse array of immune cells that are recruited continuously into lesions. They are guided into the tumor through interactions between chemokines and their receptors. A variety of chemokine receptors are expressed on the surface of both tumor and immune cells rendering them sensitive to multiple stimuli that can subsequently influence their migration and function. These features significantly impact tumor fate and are critical in melanoma control and progression. Indeed, particular chemokine receptors expressed on tumor and immune cells are strongly associated with patient prognosis. Thus, potential targeting of chemokine receptors is highly attractive as a means to quench or eliminate unconstrained tumor cell growth

Regulation of CD4+NKG2D+ Th1 cells in patients with metastatic melanoma treated with sorafenib : role of IL-15Rα and NKG2D triggering

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells.peer-reviewe

Type 2 Innate Lymphoid Cells Protect against Colorectal Cancer Progression and Predict Improved Patient Survival.

Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches

Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma

30siopenMelanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4(+) and CD8(+) T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8(+)CCR9(+) naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8(+) T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.openJacquelot N.; Enot D.P.; Flament C.; Vimond N.; Blattner C.; Pitt J.M.; Yamazaki T.; Roberti M.P.; Daillere R.; Vetizou M.; Poirier-Colame V.; Semeraro M.; Caignard A.; Slingluff C.L.; Sallusto F.; Rusakiewicz S.; Weide B.; Marabelle A.; Kohrt H.; Dalle S.; Cavalcanti A.; Kroemer G.; DI Giacomo A.M.; Maio M.; Wong P.; Yuan J.; Wolchok J.; Umansky V.; Eggermont A.; Zitvogel L.Jacquelot, N.; Enot, D. P.; Flament, C.; Vimond, N.; Blattner, C.; Pitt, J. M.; Yamazaki, T.; Roberti, M. P.; Daillere, R.; Vetizou, M.; Poirier-Colame, V.; Semeraro, M.; Caignard, A.; Slingluff, C. L.; Sallusto, F.; Rusakiewicz, S.; Weide, B.; Marabelle, A.; Kohrt, H.; Dalle, S.; Cavalcanti, A.; Kroemer, G.; DI Giacomo, A. M.; Maio, M.; Wong, P.; Yuan, J.; Wolchok, J.; Umansky, V.; Eggermont, A.; Zitvogel, L

Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma

Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches

The Immune System in Metastatic Melanoma : Prognostic and Predictive Roles.

Le mélanome métastatique reste un enjeu majeur de santé publique. Les avancées fulgurantes de ces dernières années ont permis d’améliorer la prise en charge thérapeutique, notamment avec l’arrivée des anticorps bloquant ou agonistiques ciblant les molécules de co-inhibition ou de co-stimulation. Cependant, certains patients sont réfractaires à tout traitement. Il est donc nécessaire de mettre en évidence l’importance de certains paramètres immunologiques permettant d’améliorer le suivi des patients de stade III à haut risque de récidive. De plus, il est primordial de découvrir des marqueurs prédictifs associés à la réponse à ces différents traitements immunomodulateurs. Nous avons identifié une association entre une fréquence élevée de CD45RA+CD4+ et de CD3-CD56- au sein des métastases ganglionnaires avec la survenue d’une récidive anticipée.Une forte expression de NKG2D à la surface des lymphocytes T CD8+, une faible proportion de Tregs ou une faible expression de PD-L1 à la surface des T circulants sont associées à une meilleure survie. Aussi, la mise en place d’un test in-vitro étudiant les réactivités fonctionnelles des lymphocytes infiltrant les tumeurs a permis de dégager l’importance de l’expression de CD95/Fas sur les T CD4+ circulants et de CD137/4-1BB sur les T CD8+ circulants dans la prédiction de la réponse à l’ipilimumab (anti-CTLA-4) et à la combinaison ipilimumab + nivolumab (anti-PD-1). Par ailleurs, le pattern d’expression des récepteurs de chimiokines à la surface des lymphocytes T périphériques permet de détecter les localisations métastatiques de mélanome. Cette étude a révélé également l’importance biologique de l’axe CCR9/CCL25 dans l’immunosurveillance naturelle anti-tumorale.Metastatic melanoma (MM) is an unmet medical need. The development of immune checkpoint blockers (ICB) improved patient’s clinical outcomes. However, some patients still do not respond to these therapies. To adress these issues, we must find some immunological parameters which predict the relapse of high risk resected stage III melanoma patients. Moreover, it is an urgent need to identify some predicting parameters to these ICB. In our studies, high frequencies of CD45RA+CD4+ and CD3-CD56- in metastatic lymph nodes are associated with a short relapse-free survival. Higher expression of NKG2D on CD8 T cells, low Tregs and low PD-L1 expression on circulating T cells are associated with a prolonged overall survival.Furthermore, we designed an in-vitro test to assess intratumor lymphocytes reactivities to ICB and cytokines (IL-2 and IFNα2a). Low expression of CD95/Fas on CD4+ circulating T cells and high expression of CD137/4-1BB on circulating CD8+ T cells are associated with the response to ipilimumab (anti-CTLA-4) and to the combination ipilimumab + nivolumab (anti-PD-1), respectively. In addition, the chemokine receptor pattern expressed at the surface of circulating lymphocytes could predict the metastatic spreading of melanoma. In this last study, we demonstrated the critical role of CCR9/CCL25 pathway in the natural anti-cancer immune surveillance

Immune Checkpoints and Innate Lymphoid Cells—New Avenues for Cancer Immunotherapy

Immune checkpoints (IC) are broadly characterized as inhibitory pathways that tightly regulate the activation of the immune system. These molecular “brakes” are centrally involved in the maintenance of immune self-tolerance and represent a key mechanism in avoiding autoimmunity and tissue destruction. Antibody-based therapies target these inhibitory molecules on T cells to improve their cytotoxic function, with unprecedented clinical efficacies for a number of malignancies. Many of these ICs are also expressed on innate lymphoid cells (ILC), drawing interest from the field to understand their function, impact for anti-tumor immunity and potential for immunotherapy. In this review, we highlight ILC specificities at different tissue sites and their migration potential upon inflammatory challenge. We further summarize the current understanding of IC molecules on ILC and discuss potential strategies for ILC modulation as part of a greater anti-cancer armamentarium

Designer : carrières et professionnalisation - Designer: careers and professionalization

Les écoles de design se sont professionnalisées. Leur objectif n'est plus de former uniquement des créatifs mais bien des professionnels de la création, employables et évolutifs. Se former dans de telles écoles est un investissement professionnel qui mène à 40 ans de création au service des usages, du développement et du progrès. Le designer : Qui est ce professionnel ? Où travaille-t-il, avec quelles responsabilités, avec quels objectifs ? Quel parcours emprunte-t-il 5 ans, 10 ans, 15 ans après sa formation ? En révélant le designer comme ressource humaine, ce livre ouvre les possibles en termes de carrières design au travers de 62 entretiens et portraits de designers internationaux et d'analyses de professionnels sur les compétences et les profils de ceux qui se sont formés au design dans les écoles du réseau Cumulus

Innate lymphoid cells and cancer

The innate lymphoid cell (ILC) family is composed of natural killer (NK) cells, ILC1, ILC2 and ILC3, which participate in immune responses to virus, bacteria, parasites and transformed cells. ILC1, ILC2 and ILC3 subsets are mostly tissue-resident, and are profoundly imprinted by their organ of residence. They exhibit pleiotropic effects, driving seemingly paradoxical responses such as tissue repair and, alternatively, immunopathology toward allergens and promotion of tumorigenesis. Despite this, a trickle of studies now suggests that non-NK ILCs may not be overwhelmingly tumorigenic and could potentially be harnessed to drive anti-tumor responses. Here, we examine the pleiotropic behavior of ILCs in cancer and begin to unravel the gap in our knowledge that exposes a new horizon for thinking about modifying ILCs and targeting them for immunotherapy