Cold Tumors: A Therapeutic Challenge for Immunotherapy

Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called “cold tumors.” In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition, ‘‘supra-physiological’’ therapies, such as T cell recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism involved, especially in MHC class I negative tumors. The determination of the main factors implicated in the lack of preexisting tumor T cell infiltration is crucial for the development of adapted algorithms of treatments for cold tumors

Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection

Background and aims: Chronic hepatitis B virus (HBV) infection is a major health burden potentially evolving toward cirrhosis and hepatocellular carcinoma. HBV physiopathology is strongly related to the host immunity, yet the mechanisms of viral evasion from immune-surveillance are still misunderstood. The immune response elicited at early stages of viral infection is believed to be important for subsequent disease outcome. Dendritic cells (DCs) are crucial immune sentinels which orchestrate antiviral immunity, which offer opportunity to pathogens to subvert them to escape immunity. Despite the pivotal role of DCs in orientating antiviral responses and determining the outcome of infection, their precise involvement in HBV pathogenesis is not fully explored.Methods: One hundred thirty chronically HBV infected patients and 85 healthy donors were enrolled in the study for blood collection, together with 29 chronically HBV infected patients and 33 non-viral infected patients that were included for liver biopsy collection. In a pioneer way, we investigated the phenotypic and functional features of both circulating and intrahepatic BDCA1+ cDC2, BDCA2+ pDCs, and BDCA3+ cDC1 simultaneously in patients with chronic HBV infection by designing a unique multi-parametric flow cytometry approach.Results: We showed modulations of the frequencies and basal activation status of blood and liver DCs associated with impaired expressions of specific immune checkpoints and TLR molecules on circulating DC subsets. Furthermore, we highlighted an impaired maturation of circulating and hepatic pDCs and cDCs following stimulation with specific TLR agonists in chronic HBV patients, associated with drastic dysfunctions in the capacity of circulating DC subsets to produce IL-12p70, TNFα, IFNα, IFNλ1, and IFNλ2 while intrahepatic DCs remained fully functional. Most of these modulations correlated with HBsAg and HBV DNA levels.Conclusion: We highlight potent alterations in the distribution, phenotype and function of all DC subsets in blood together with modulations of intrahepatic DCs, revealing that HBV may hijack the immune system by subverting DCs. Our findings provide innovative insights into the immuno-pathogenesis of HBV and the mechanisms of virus escape from immune control. Such understanding is promising for developing new therapeutic strategies restoring an efficient immune control of the virus

Human Tumor-Infiltrating Dendritic Cells: From In Situ Visualization to High-Dimensional Analyses

The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different mechanisms and responses to the DC subset. Several studies identified in situ human tumor-infiltrating DCs by immunostaining using a limited number of markers. However, considering the heterogeneity of DC subsets, the identification of each subtype present in the immune infiltrate is essential. To achieve this, studies initially relied on flow cytometry analyses to provide a precise characterization of tumor-associated DC subsets based on a combination of multiple markers. The concomitant development of advanced technologies, such as mass cytometry or complete transcriptome sequencing of a cell population or at a single cell level, has provided further details on previously identified populations, has unveiled previously unknown populations, and has finally led to the standardization of the DCs classification across tissues and species. Here, we review the evolution of tumor-associated DC description, from in situ visualization to their characterization with high-dimensional technologies, and the clinical use of these findings specifically focusing on the prognostic impact of DCs in cancers

Diversification of circulating and tumor‐infiltrating plasmacytoid DCs towards the P3 (CD80 + PDL1 − )‐pDC subset negatively correlated with clinical outcomes in melanoma patients

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Alteration of the langerin oligomerization state affects Birbeck granule formation.

International audienceLangerin, a trimeric C-type lectin specifically expressed in Langerhans cells, has been reported to be a pathogen receptor through the recognition of glycan motifs by its three carbohydrate recognition domains (CRD). In the context of HIV-1 (human immunodeficiency virus-1) transmission, Langerhans cells of genital mucosa play a protective role by internalizing virions in Birbeck Granules (BG) for elimination. Langerin (Lg) is directly involved in virion binding and BG formation through its CRDs. However, nothing is known regarding the mechanism of langerin assembly underlying BG formation. We investigated at the molecular level the impact of two CRD mutations, W264R and F241L, on langerin structure, function, and BG assembly using a combination of biochemical and biophysical approaches. Although the W264R mutation causes CRD global unfolding, the F241L mutation does not affect the overall structure and gp120 (surface HIV-1 glycoprotein of 120 kDa) binding capacities of isolated Lg-CRD. In contrast, this mutation induces major functional and structural alterations of the whole trimeric langerin extracellular domain (Lg-ECD). As demonstrated by small-angle x-ray scattering comparative analysis of wild-type and mutant forms, the F241L mutation perturbs the oligomerization state and the global architecture of Lg-ECD. Correlatively, despite conserved intrinsic lectin activity of the CRD, avidity property of Lg-ECD is affected as shown by a marked decrease of gp120 binding. Beyond the change of residue itself, the F241L mutation induces relocation of the K200 side chain also located within the interface between protomers of trimeric Lg-ECD, thereby explaining the defective oligomerization of mutant Lg. We conclude that not only functional CRDs but also their correct spatial presentation are critical for BG formation as well as gp120 binding

Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection

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IL-33 drives polyfunctionality and antitumor activity of a unique ST2+ NK cell population

ARTICLE EN REVISION FAVORABLE DANS SCIENCE IMMUNOLOGYNatural Killer (NK) cell subsets differ to ensure complementary and crucial roles in tumor immunosurveillance. Their biology is critically regulated by cytokines. Here, we show that IL-33 synergizes with IL-12 to strongly activate a subset of CD56 dim NK cells acquiring ST2 expression. Transcriptomic and biological analysis of human ST2 + CD56 dim NK cells revealed a distinct intermediate differentiation state between canonical CD56 bright and CD56 dim NK cells, combining high proliferative properties, cytokines/chemokines production, and cytotoxicity. NK cells expressing ST2 protein or exhibiting a ST2-linked transcriptional signature were identified in human and mouse tumors. Accordingly, IL-12 unleashes human breast tumor ST2 + NK cell potential to produce IFN-γ in response to IL-33 and IL-33/IL-12 co-injection resulted in a NK-dependent IFN- secretion and anti-tumor effects in murine mammary tumors. An IL33 hi-NK hi score in solid tumors correlated with increased progressionfree patient survival. Our findings thus identify polyfunctional ST2 + NK cells which effector functions can be harnessed by IL-33 to boost anti-tumor immunity

IL-33 drives polyfunctionality and antitumor activity of a unique ST2+ NK cell population

ARTICLE EN REVISION FAVORABLE DANS SCIENCE IMMUNOLOGYNatural Killer (NK) cell subsets differ to ensure complementary and crucial roles in tumor immunosurveillance. Their biology is critically regulated by cytokines. Here, we show that IL-33 synergizes with IL-12 to strongly activate a subset of CD56 dim NK cells acquiring ST2 expression. Transcriptomic and biological analysis of human ST2 + CD56 dim NK cells revealed a distinct intermediate differentiation state between canonical CD56 bright and CD56 dim NK cells, combining high proliferative properties, cytokines/chemokines production, and cytotoxicity. NK cells expressing ST2 protein or exhibiting a ST2-linked transcriptional signature were identified in human and mouse tumors. Accordingly, IL-12 unleashes human breast tumor ST2 + NK cell potential to produce IFN-γ in response to IL-33 and IL-33/IL-12 co-injection resulted in a NK-dependent IFN- secretion and anti-tumor effects in murine mammary tumors. An IL33 hi-NK hi score in solid tumors correlated with increased progressionfree patient survival. Our findings thus identify polyfunctional ST2 + NK cells which effector functions can be harnessed by IL-33 to boost anti-tumor immunity

BDCA1 + cDC2s, BDCA2 + pDCs and BDCA3 + cDC1s reveal distinct pathophysiologic features and impact on clinical outcomes in melanoma patients

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