Immunometabolic mechanisms involved in human gamma delta T cell activation in cancer.

Les lymphocytes T gamma delta sont des sentinelles des barrières épithéliales qui jouent un rôle majeur dans la défense contre les agressions. Dans le cancer, elles participent à l'immunosurveillance et leur présence au sein du stroma tumoral constitue le principal facteur pronostic positif. Il s’agit donc d’une population qui pourrait constituer une cible thérapeutique privilégiée en oncoimmunologie. La fonction des LTgd est finement régulée par un ensemble de cytokines et en particulier par l’interleukine 18 (IL-18). L’IL-18 est une cytokine proinflammatoire correspondant à l’un des plus puissants stimulateurs solubles des LTgd, impliquée dans l’homéostasie tissulaire au niveau des barrières épithéliales. Elle est sécrétée grâce à l’activation de l’inflammasome, complexe cytosolique composé de Nod-Like Receptors (NLRs). Néanmoins, in vitro, certaines lignées cancéreuses n’en sécrètent plus, probablement du fait de la perte d'expression des constituants de l'inflammasome.Nous avons donc voulu évaluer l’expression protéique in vivo des constituants des inflammasomes, et leur impact pronostic en clinique. L’expression protéique a été analysée dans 104 tumeurs colorectales appariées aux tissus sains, par immunofluorescence sur un tissue micro-array (TMA). Un comarquage de la cytokératine a été effectué pour évaluer l’expression de ces composants spécifiquement dans les cellules épithéliales, qu’elles soient tumorales ou saines. Nos résultats ont montré une diminution de l’expression de l’ensemble des constituants de l’inflammasome dans l’épithélium des tissus tumoraux, ainsi que de la caspase-1 et des interleukines. Néanmoins, seules les pertes d’expression de NLRC4, de NLRP6 ou de l’IL-18 étaient associées à une maladie plus avancée ainsi qu’à la mortalité des patients. De plus, la perte combinée de ces 3 marqueurs était associée à un pronostic encore plus mauvais. Ainsi, seulement 22.2% des patients NLRC4bas/NLRP6bas/IL-18bas étaient encore vivants à 5 ans contre 85.2% pour les patients NLRC4haut/NLRP6haut/IL-18haut. De plus, la perte d’expression de NLRC4 et de l’IL-18 semblait corrélée à une diminution plus importante de l’infiltrat en cellules immunitaires et en particulier en lymphocytes T CD3+. Nous avons également montré grâce à un modèle in vitro que la réexpression de NLRC4 était associée à une diminution de la prolifération des cellules tumorales coliques métastatiques. Enfin, en trancriptomique, cette réexpression de NLRC4 induisait l’expression de médiateurs de la voie de l’interféron de type I. Dans l’ensemble, ces résultats montrent que la perte d’expression protéique de NLRC4, NLRP6 et IL-18 par la tumeur pourrait constituer un mécanisme de résistance à l’immunité antitumorale et semblerait être un facteur pronostic majeur.Dans un second temps, nous avons étudié la régulation des LTgd par des molécules solubles non cytokiniques, dépendantes du métabolisme tumorale. Ainsi, nous avons montré que l’activation de l’AMPK dans les cellules cancéreuses de côlon permettait d’augmenter l’expression d’un antigène de stress appelé EphA2 reconnu par les LTgd humains. De plus, l’induction in vitro de l'activation de l’AMPK permettait la sécrétion de petits peptides qui modulent la réponse immunitaire. Ainsi, par une série de chromatographies sur les surnageants de cellules tumorales reprogrammées, nous avons pu identifier un peptide capable d’inhiber l’activation des LB in vitro. Nous tentons actuellement d’identifier d’autres cibles immunitaires, mais également d’identifier les mécanismes qui induisent cet effet.Ces 2 axes constituent autant de cibles potentielles en thérapeutiques anticancéreuse, seules ou en association avec les chimiothérapies ou avec les immunothérapies actuelles. Ceci pourrait ainsi permettre d’améliorer les réponses observées dans les cancers.Gamma delta (γδ) T cells are sentinels of the intestinal barrier, protecting the host from aggressions. In cancer, they have a crucial role in immunosurveillance and the stromal infiltration of γδ T cells is the more important prognostic factor among all immune cells. Indeed, this population could be an interesting therapeutic target in oncoimmunology. The activation of γδ T cells is tightly regulated by several cytokines and especially interleukin-18 (IL-18). IL-18 is a proinflammatory cytokine corresponding to the most powerful soluble activator of γδ T cells, involved in tissue homeostasis in the epithelial barriers. It is secreted through the activation of the inflammasome, a cytosolic complex consisting in Nod-Like Receptors (NLRs). However, in vitro, some cancer cell lines do not secrete IL-18, probably due to a loss of expression and/or activation of inflammasome components. We have assessed the protein expression in vivo of inflammasome components, and their correlation with clinical outcome of colorectal cancer patients. The expression was evaluated in 104 colorectal tumours, matched with normal tissue for each patient, through an immunofluorescence assay on a tissue micro-array (TMA). We also performed a cytokeratin staining to assess the expression of each components specifically in epithelial cells from tumour or normal tissue. We showed a decreased expression of all inflammasome components, including caspase-1 and cytokines, in the tumour epithelium compared to normal tissue. However, only the expressions of NLRC4, NLRP6 or IL-18 were associated to a more aggressive disease and to a worse outcome. Furthermore, combined downregulation of these 3 components was correlated to a poor prognosis. Indeed, only 22.2% of patients NLRC4low/NLRP6low/IL-18low were still alive after 5 years, versus 85.2% for NLRC4high/NLRP6high/IL18high patients. Furthermore, the downregulation of NLRC4 and IL-18 was associated with a decreased immune infiltration especially for CD3 positive T cells. We also showed in vitro that NLRC4 reexpression was associated to a decreased proliferation of metastatic colon cancer cell line. Finally, at a transcriptomic level, the expression of NLRC4 in these cell lines was correlated to an interferon type I signature. All these results show that the downregulation of NLRC4, NLRP6 and IL-18 by tumour cells could constitute a resistance mechanism to the antitumor immune response and seems to be an important prognostic factor. The activation of γδ T cells could also been regulated by molecules that are not cytokines, depending on tumour metabolism. Indeed, we showed that the activation of AMPK in colon cancer cell lines induced the expression of the stress antigen receptor EphA2, recognised by human γδ T lymphocytes. Furthermore, the in vitro induction of AMPK activation favoured the released of small soluble molecules that modulate the immune response. Indeed, after several chromatography of the supernatant from reprogrammed cancer cell lines, we have identified a peptide that is able to inhibit the activation of B cells in an in vitro model. We are trying to identify the mechanisms underlying this inhibition. In conclusion, we have identify potential therapeutic targets in cancer treatment, alone or in association with chemotherapies and/or immunotherapies. This could help to improve antitumor immune response and patient outcomes

Immunometabolic mechanisms involved in human gamma delta T cell activation in cancer.

Les lymphocytes T gamma delta sont des sentinelles des barrières épithéliales qui jouent un rôle majeur dans la défense contre les agressions. Dans le cancer, elles participent à l'immunosurveillance et leur présence au sein du stroma tumoral constitue le principal facteur pronostic positif. Il s’agit donc d’une population qui pourrait constituer une cible thérapeutique privilégiée en oncoimmunologie. La fonction des LTgd est finement régulée par un ensemble de cytokines et en particulier par l’interleukine 18 (IL-18). L’IL-18 est une cytokine proinflammatoire correspondant à l’un des plus puissants stimulateurs solubles des LTgd, impliquée dans l’homéostasie tissulaire au niveau des barrières épithéliales. Elle est sécrétée grâce à l’activation de l’inflammasome, complexe cytosolique composé de Nod-Like Receptors (NLRs). Néanmoins, in vitro, certaines lignées cancéreuses n’en sécrètent plus, probablement du fait de la perte d'expression des constituants de l'inflammasome.Nous avons donc voulu évaluer l’expression protéique in vivo des constituants des inflammasomes, et leur impact pronostic en clinique. L’expression protéique a été analysée dans 104 tumeurs colorectales appariées aux tissus sains, par immunofluorescence sur un tissue micro-array (TMA). Un comarquage de la cytokératine a été effectué pour évaluer l’expression de ces composants spécifiquement dans les cellules épithéliales, qu’elles soient tumorales ou saines. Nos résultats ont montré une diminution de l’expression de l’ensemble des constituants de l’inflammasome dans l’épithélium des tissus tumoraux, ainsi que de la caspase-1 et des interleukines. Néanmoins, seules les pertes d’expression de NLRC4, de NLRP6 ou de l’IL-18 étaient associées à une maladie plus avancée ainsi qu’à la mortalité des patients. De plus, la perte combinée de ces 3 marqueurs était associée à un pronostic encore plus mauvais. Ainsi, seulement 22.2% des patients NLRC4bas/NLRP6bas/IL-18bas étaient encore vivants à 5 ans contre 85.2% pour les patients NLRC4haut/NLRP6haut/IL-18haut. De plus, la perte d’expression de NLRC4 et de l’IL-18 semblait corrélée à une diminution plus importante de l’infiltrat en cellules immunitaires et en particulier en lymphocytes T CD3+. Nous avons également montré grâce à un modèle in vitro que la réexpression de NLRC4 était associée à une diminution de la prolifération des cellules tumorales coliques métastatiques. Enfin, en trancriptomique, cette réexpression de NLRC4 induisait l’expression de médiateurs de la voie de l’interféron de type I. Dans l’ensemble, ces résultats montrent que la perte d’expression protéique de NLRC4, NLRP6 et IL-18 par la tumeur pourrait constituer un mécanisme de résistance à l’immunité antitumorale et semblerait être un facteur pronostic majeur.Dans un second temps, nous avons étudié la régulation des LTgd par des molécules solubles non cytokiniques, dépendantes du métabolisme tumorale. Ainsi, nous avons montré que l’activation de l’AMPK dans les cellules cancéreuses de côlon permettait d’augmenter l’expression d’un antigène de stress appelé EphA2 reconnu par les LTgd humains. De plus, l’induction in vitro de l'activation de l’AMPK permettait la sécrétion de petits peptides qui modulent la réponse immunitaire. Ainsi, par une série de chromatographies sur les surnageants de cellules tumorales reprogrammées, nous avons pu identifier un peptide capable d’inhiber l’activation des LB in vitro. Nous tentons actuellement d’identifier d’autres cibles immunitaires, mais également d’identifier les mécanismes qui induisent cet effet.Ces 2 axes constituent autant de cibles potentielles en thérapeutiques anticancéreuse, seules ou en association avec les chimiothérapies ou avec les immunothérapies actuelles. Ceci pourrait ainsi permettre d’améliorer les réponses observées dans les cancers.Gamma delta (γδ) T cells are sentinels of the intestinal barrier, protecting the host from aggressions. In cancer, they have a crucial role in immunosurveillance and the stromal infiltration of γδ T cells is the more important prognostic factor among all immune cells. Indeed, this population could be an interesting therapeutic target in oncoimmunology. The activation of γδ T cells is tightly regulated by several cytokines and especially interleukin-18 (IL-18). IL-18 is a proinflammatory cytokine corresponding to the most powerful soluble activator of γδ T cells, involved in tissue homeostasis in the epithelial barriers. It is secreted through the activation of the inflammasome, a cytosolic complex consisting in Nod-Like Receptors (NLRs). However, in vitro, some cancer cell lines do not secrete IL-18, probably due to a loss of expression and/or activation of inflammasome components. We have assessed the protein expression in vivo of inflammasome components, and their correlation with clinical outcome of colorectal cancer patients. The expression was evaluated in 104 colorectal tumours, matched with normal tissue for each patient, through an immunofluorescence assay on a tissue micro-array (TMA). We also performed a cytokeratin staining to assess the expression of each components specifically in epithelial cells from tumour or normal tissue. We showed a decreased expression of all inflammasome components, including caspase-1 and cytokines, in the tumour epithelium compared to normal tissue. However, only the expressions of NLRC4, NLRP6 or IL-18 were associated to a more aggressive disease and to a worse outcome. Furthermore, combined downregulation of these 3 components was correlated to a poor prognosis. Indeed, only 22.2% of patients NLRC4low/NLRP6low/IL-18low were still alive after 5 years, versus 85.2% for NLRC4high/NLRP6high/IL18high patients. Furthermore, the downregulation of NLRC4 and IL-18 was associated with a decreased immune infiltration especially for CD3 positive T cells. We also showed in vitro that NLRC4 reexpression was associated to a decreased proliferation of metastatic colon cancer cell line. Finally, at a transcriptomic level, the expression of NLRC4 in these cell lines was correlated to an interferon type I signature. All these results show that the downregulation of NLRC4, NLRP6 and IL-18 by tumour cells could constitute a resistance mechanism to the antitumor immune response and seems to be an important prognostic factor. The activation of γδ T cells could also been regulated by molecules that are not cytokines, depending on tumour metabolism. Indeed, we showed that the activation of AMPK in colon cancer cell lines induced the expression of the stress antigen receptor EphA2, recognised by human γδ T lymphocytes. Furthermore, the in vitro induction of AMPK activation favoured the released of small soluble molecules that modulate the immune response. Indeed, after several chromatography of the supernatant from reprogrammed cancer cell lines, we have identified a peptide that is able to inhibit the activation of B cells in an in vitro model. We are trying to identify the mechanisms underlying this inhibition. In conclusion, we have identify potential therapeutic targets in cancer treatment, alone or in association with chemotherapies and/or immunotherapies. This could help to improve antitumor immune response and patient outcomes

Identification des mécanismes immunométaboliques impliqués dans l’activation des lymphocytes T γδ tissulaires humains dans le cancer

Gamma delta (γδ) T cells are sentinels of the intestinal barrier, protecting the host from aggressions. In cancer, they have a crucial role in immunosurveillance and the stromal infiltration of γδ T cells is the more important prognostic factor among all immune cells. Indeed, this population could be an interesting therapeutic target in oncoimmunology. The activation of γδ T cells is tightly regulated by several cytokines and especially interleukin-18 (IL-18). IL-18 is a proinflammatory cytokine corresponding to the most powerful soluble activator of γδ T cells, involved in tissue homeostasis in the epithelial barriers. It is secreted through the activation of the inflammasome, a cytosolic complex consisting in Nod-Like Receptors (NLRs). However, in vitro, some cancer cell lines do not secrete IL-18, probably due to a loss of expression and/or activation of inflammasome components. We have assessed the protein expression in vivo of inflammasome components, and their correlation with clinical outcome of colorectal cancer patients. The expression was evaluated in 104 colorectal tumours, matched with normal tissue for each patient, through an immunofluorescence assay on a tissue micro-array (TMA). We also performed a cytokeratin staining to assess the expression of each components specifically in epithelial cells from tumour or normal tissue. We showed a decreased expression of all inflammasome components, including caspase-1 and cytokines, in the tumour epithelium compared to normal tissue. However, only the expressions of NLRC4, NLRP6 or IL-18 were associated to a more aggressive disease and to a worse outcome. Furthermore, combined downregulation of these 3 components was correlated to a poor prognosis. Indeed, only 22.2% of patients NLRC4low/NLRP6low/IL-18low were still alive after 5 years, versus 85.2% for NLRC4high/NLRP6high/IL18high patients. Furthermore, the downregulation of NLRC4 and IL-18 was associated with a decreased immune infiltration especially for CD3 positive T cells. We also showed in vitro that NLRC4 reexpression was associated to a decreased proliferation of metastatic colon cancer cell line. Finally, at a transcriptomic level, the expression of NLRC4 in these cell lines was correlated to an interferon type I signature. All these results show that the downregulation of NLRC4, NLRP6 and IL-18 by tumour cells could constitute a resistance mechanism to the antitumor immune response and seems to be an important prognostic factor. The activation of γδ T cells could also been regulated by molecules that are not cytokines, depending on tumour metabolism. Indeed, we showed that the activation of AMPK in colon cancer cell lines induced the expression of the stress antigen receptor EphA2, recognised by human γδ T lymphocytes. Furthermore, the in vitro induction of AMPK activation favoured the released of small soluble molecules that modulate the immune response. Indeed, after several chromatography of the supernatant from reprogrammed cancer cell lines, we have identified a peptide that is able to inhibit the activation of B cells in an in vitro model. We are trying to identify the mechanisms underlying this inhibition. In conclusion, we have identify potential therapeutic targets in cancer treatment, alone or in association with chemotherapies and/or immunotherapies. This could help to improve antitumor immune response and patient outcomes.Les lymphocytes T gamma delta sont des sentinelles des barrières épithéliales qui jouent un rôle majeur dans la défense contre les agressions. Dans le cancer, elles participent à l'immunosurveillance et leur présence au sein du stroma tumoral constitue le principal facteur pronostic positif. Il s’agit donc d’une population qui pourrait constituer une cible thérapeutique privilégiée en oncoimmunologie. La fonction des LTgd est finement régulée par un ensemble de cytokines et en particulier par l’interleukine 18 (IL-18). L’IL-18 est une cytokine proinflammatoire correspondant à l’un des plus puissants stimulateurs solubles des LTgd, impliquée dans l’homéostasie tissulaire au niveau des barrières épithéliales. Elle est sécrétée grâce à l’activation de l’inflammasome, complexe cytosolique composé de Nod-Like Receptors (NLRs). Néanmoins, in vitro, certaines lignées cancéreuses n’en sécrètent plus, probablement du fait de la perte d'expression des constituants de l'inflammasome.Nous avons donc voulu évaluer l’expression protéique in vivo des constituants des inflammasomes, et leur impact pronostic en clinique. L’expression protéique a été analysée dans 104 tumeurs colorectales appariées aux tissus sains, par immunofluorescence sur un tissue micro-array (TMA). Un comarquage de la cytokératine a été effectué pour évaluer l’expression de ces composants spécifiquement dans les cellules épithéliales, qu’elles soient tumorales ou saines. Nos résultats ont montré une diminution de l’expression de l’ensemble des constituants de l’inflammasome dans l’épithélium des tissus tumoraux, ainsi que de la caspase-1 et des interleukines. Néanmoins, seules les pertes d’expression de NLRC4, de NLRP6 ou de l’IL-18 étaient associées à une maladie plus avancée ainsi qu’à la mortalité des patients. De plus, la perte combinée de ces 3 marqueurs était associée à un pronostic encore plus mauvais. Ainsi, seulement 22.2% des patients NLRC4bas/NLRP6bas/IL-18bas étaient encore vivants à 5 ans contre 85.2% pour les patients NLRC4haut/NLRP6haut/IL-18haut. De plus, la perte d’expression de NLRC4 et de l’IL-18 semblait corrélée à une diminution plus importante de l’infiltrat en cellules immunitaires et en particulier en lymphocytes T CD3+. Nous avons également montré grâce à un modèle in vitro que la réexpression de NLRC4 était associée à une diminution de la prolifération des cellules tumorales coliques métastatiques. Enfin, en trancriptomique, cette réexpression de NLRC4 induisait l’expression de médiateurs de la voie de l’interféron de type I. Dans l’ensemble, ces résultats montrent que la perte d’expression protéique de NLRC4, NLRP6 et IL-18 par la tumeur pourrait constituer un mécanisme de résistance à l’immunité antitumorale et semblerait être un facteur pronostic majeur.Dans un second temps, nous avons étudié la régulation des LTgd par des molécules solubles non cytokiniques, dépendantes du métabolisme tumorale. Ainsi, nous avons montré que l’activation de l’AMPK dans les cellules cancéreuses de côlon permettait d’augmenter l’expression d’un antigène de stress appelé EphA2 reconnu par les LTgd humains. De plus, l’induction in vitro de l'activation de l’AMPK permettait la sécrétion de petits peptides qui modulent la réponse immunitaire. Ainsi, par une série de chromatographies sur les surnageants de cellules tumorales reprogrammées, nous avons pu identifier un peptide capable d’inhiber l’activation des LB in vitro. Nous tentons actuellement d’identifier d’autres cibles immunitaires, mais également d’identifier les mécanismes qui induisent cet effet.Ces 2 axes constituent autant de cibles potentielles en thérapeutiques anticancéreuse, seules ou en association avec les chimiothérapies ou avec les immunothérapies actuelles. Ceci pourrait ainsi permettre d’améliorer les réponses observées dans les cancers

Control of the Antitumor Immune Response by Cancer Metabolism

The metabolic reprogramming of tumor cells and immune escape are two major hallmarks of cancer cells. The metabolic changes that occur during tumorigenesis, enabling survival and proliferation, are described for both solid and hematological malignancies. Concurrently, tumor cells have deployed mechanisms to escape immune cell recognition and destruction. Additionally, therapeutic blocking of tumor-mediated immunosuppression has proven to have an unprecedented positive impact in clinical oncology. Increased evidence suggests that cancer metabolism not only plays a crucial role in cancer signaling for sustaining tumorigenesis and survival, but also has wider implications in the regulation of antitumor immune signaling through both the release of signaling molecules and the expression of immune membrane ligands. Here, we review these molecular events to highlight the contribution of cancer cell metabolic reprogramming on the shaping of the antitumor immune response

Metabolic Stress in the Immune Function of T Cells, Macrophages and Dendritic Cells

Innate and adaptive immune cells from myeloid and lymphoid lineages resolve host infection or cell stress by mounting an appropriate and durable immune response. Upon sensing of cellular insults, immune cells become activated and undergo rapid and efficient functional changes to unleash biosynthesis of macromolecules, proliferation, survival, and trafficking; unprecedented events among other mammalian cells within the host. These changes must become operational within restricted timing to rapidly control the insult and to avoid tissue damage and pathogen spread. Such changes occur at high energy cost. Recent advances have established that plasticity of immune functions occurs in distinct metabolic stress features. Evidence has accumulated to indicate that specific metabolic signatures dictate appropriate immune functions in both innate and adaptive immunity. Importantly, recent studies have shed light on whether successfully manipulating particular metabolic targets is sufficient to modulate immune function and polarization, thereby offering strong therapeutic potential for various common immune-mediated diseases, including inflammation and autoimmune-associated diseases and cancer. In this review, we detail how cellular metabolism controls immune function and phenotype within T cells and macrophages particularly, and the distinct molecular metabolic programming and targets instrumental to engage this regulation

Editorial: Tumor-promoting immune cells: Cancer immune escape and beyond

International audienceNo abstract availabl

Beyond Immunosuppression: The Multifaceted Functions of Tumor-Promoting Myeloid Cells in Breast Cancers

International audienceBreast cancers are commonly associated with an immunosuppressive microenvironment responsible for tumor escape from anti-cancer immunity. Cells of the myeloid lineage account for a major part of this tumor-promoting landscape. These myeloid cells are composed of heterogeneous subsets at different stages of differentiation and have traditionally been described by their cardinal ability to suppress innate and adaptive anticancer immunity. However, evidence has accumulated that, beyond their immunosuppressive properties, breast cancer-induced myeloid cells are also equipped with a broad array of “non-immunological” tumor-promoting functions. They therefore represent major impediments for anticancer therapies, particularly for immune-based interventions. We herein analyze and discuss current literature related to the versatile properties of the different myeloid cell subsets engaged in breast cancer development. We critically assess persisting difficulties and challenges in unequivocally discriminate dedicated subsets, which has so far prevented both the selective targeting of these immunosuppressive cells and their use as potential biomarkers. In this context, we propose the concept of IMCGL, “pro-tumoral immunosuppressive myeloid cells of the granulocytic lineage”, to more accurately reflect the contentious nature and origin of granulocytic cells in the breast tumor microenvironment. Future research prospects related to the role of this myeloid landscape in breast cancer are further considered

Hormone Receptor Signaling and Breast Cancer Resistance to Anti-Tumor Immunity

International audienceBreast cancers regroup many heterogeneous diseases unevenly responding to currently available therapies. Approximately 70–80% of breast cancers express hormone (estrogen or progesterone) receptors. Patients with these hormone-dependent breast malignancies benefit from therapies targeting endocrine pathways. Nevertheless, metastatic disease remains a major challenge despite available treatments, and relapses frequently ensue. By improving patient survival and quality of life, cancer immunotherapies have sparked considerable enthusiasm and hope in the last decade but have led to only limited success in breast cancers. In addition, only patients with hormone-independent breast cancers seem to benefit from these immune-based approaches. The present review examines and discusses the current literature related to the role of hormone receptor signaling (specifically, an estrogen receptor) and the impact of its modulation on the sensitivity of breast cancer cells to the effector mechanisms of anti-tumor immune responses and on the capability of breast cancers to escape from protective anti-cancer immunity. Future research prospects related to the possibility of promoting the efficacy of immune-based interventions using hormone therapy agents are considered

Combinations of Anti-Angiogenic Agents and Immune Checkpoint Inhibitors in Renal Cell Carcinoma: Best Option?

Over the past decade, major advances have been made in the treatment of advanced and metastatic renal cell carcinomas, specifically clear cell carcinomas. For many years the optimal approach was sequential; thus, monotherapies [principally tyrosine kinase inhibitors (TKIs)] targeting angiogenesis until toxicity or progressive disease developed. The rationale was the common mechanisms of action of the targeting agents and avoidance of the risk of overlapping toxicities. Immune checkpoint inhibitors (ICIs) are effective monotherapies, and combinations thereof with anti-angiogenic agents were thus later considered. Synergistic interactions were reported in vitro. Clinical efficacy was evident in three pivotal phase III trials with axitinib-pembrolizumab, cabozantinib-nivolumab, and lenvatinib-pembrolizumab combinations. Two other combinations showed interesting results but did not improve overall survival. However, the data aided our understanding of the new therapeutic approaches. A combination of the ICIs nivolumab and ipilimumab was the first to evidence better progression-free and overall survival compared to sunitinib in patients with intermediate or unfavourable prognoses as evaluated by the International mRCC Database Consortium (IMDC). Here we focus on the TKI-ICI combinations, emphasising the rationale of their use and the clinical results. To date, no biomarker facilitating the selection of an optimal treatment by disease and patient status has been reported

Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010–2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival