Journal Articles

Molecular patterns of resistance to immune checkpoint blockade in melanoma

(1) Lauss M (2) Phung B (3) Borch TH (4) Harbst K (5) Kaminska K (6) Ebbesson A (7) Hedenfalk I (8) Yuan J (9) Nielsen K (10) Ingvar C (11) Carneiro A (12) Isaksson K (13) Pietras K (14) Svane IM (15) Donia M (16) Jönsson G

Nature communications | Free PMC Article

Lauss et al. analyzed the tumor cell-intrinsic and immune TME features of human melanoma specimens collected after progression on ICB, and highlighted that anti-CTLA-4 and anti-PD-1 resistance occur through different molecular mechanisms. Genetic alterations in antigen presentation or IFNγ pathway genes accounted for 26% of the cases. Anti-CTLA-4-resistant tumors showed an increased number of expanded TCR clones, along with increased Foxp3+ T cells compared to anti-PD-1-resistant samples. Anti-PD-1-resistant tumors were enriched in MITFlowB2M− dedifferentiated melanoma cells and had fewer, mainly PD1-TCF7-, infiltrating CD8+ T cells.

Contributed by Shishir Pant

(1) Lauss M (2) Phung B (3) Borch TH (4) Harbst K (5) Kaminska K (6) Ebbesson A (7) Hedenfalk I (8) Yuan J (9) Nielsen K (10) Ingvar C (11) Carneiro A (12) Isaksson K (13) Pietras K (14) Svane IM (15) Donia M (16) Jönsson G

Nature communications | Free PMC Article

Lauss et al. analyzed the tumor cell-intrinsic and immune TME features of human melanoma specimens collected after progression on ICB, and highlighted that anti-CTLA-4 and anti-PD-1 resistance occur through different molecular mechanisms. Genetic alterations in antigen presentation or IFNγ pathway genes accounted for 26% of the cases. Anti-CTLA-4-resistant tumors showed an increased number of expanded TCR clones, along with increased Foxp3+ T cells compared to anti-PD-1-resistant samples. Anti-PD-1-resistant tumors were enriched in MITFlowB2M− dedifferentiated melanoma cells and had fewer, mainly PD1-TCF7-, infiltrating CD8+ T cells.

Contributed by Shishir Pant

ABSTRACT: Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collect biopsies from a cohort of 44 patients with melanoma after progression on anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways are observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions have a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and T cell receptor (TCR) clonality analyses. One anti-PD1 resistant lesion harbors a distinct immune cell niche, however, anti-PD1 resistant tumors are generally immune poor with non-expanded TCR clones. Such immune poor microenvironments are associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors have reduced fractions of PD1(+) CD8(+) T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.

Author Info: (1) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (2) Divisio

Author Info: (1) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (2) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (3) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (4) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (5) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (6) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (7) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Lund University Cancer Center, LUCC, Lund, Sweden. (8) Division of Molecular Hematology, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (9) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Dermatology, SkŒne University Hospital and Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (10) Division of Surgery, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (11) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Department of Hematology, Oncology and Radiation Physics, SkŒne University Hospital Comprehensive Cancer Center, 22185, Lund, Sweden. (12) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Surgery, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. Department of Surgery, Kristianstad Hospital, 29133, Kristianstad, Sweden. (13) Lund University Cancer Center, LUCC, Lund, Sweden. Division of Translational Cancer Research, Department of Laboratory Medicine, Faculty of Medicine, Lund University, 22185, Lund, Sweden. (14) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (15) National Center for Cancer Immune Therapy, Department of Oncology, Copenhagen University Hospital, Herlev, Denmark. (16) Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, 22185, Lund, Sweden. goran_b.jonsson@med.lu.se. Lund University Cancer Center, LUCC, Lund, Sweden. goran_b.jonsson@med.lu.se.

Citation: Nat Commun 2024 Apr 9 15:3075 Epub04/09/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38594286

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Myeloid-T cell interplay and cell state transitions associated with checkpoint inhibitor response in melanoma

(1) Schlenker R (2) Schwalie PC (3) Dettling S (4) Huesser T (5) Irmisch A (6) Mariani M (7) Martínez Gómez JM (8) Ribeiro A (9) Limani F (10) Herter S (11) Yángüez E (12) Hoves S (13) Somandin J (14) Siebourg-Polster J (15) Kam-Thong T (16) de Matos IG (17) Umana P (18) Dummer R (19) Levesque MP (20) Bacac M

Med

Using scRNAseq, Schlenker and Schwalie et al. analyzed peripheral blood cells and cells infiltrating tumors surgically resected from 22 patients with stage III–IV metastatic melanoma who subsequently received CPI therapy. CPI responders exhibited high levels of circulating classical and tumor-infiltrating monocytes, which preferentially transitioned to M1-like macrophages in tumors. In CPI responders, myeloid–T/NK cell interactions were proinflammatory and supported T cell priming and effector activities. In CPI non-responders, myeloid–T/NK cell interactions were immunosuppressive, and CD8+ TILs tended to express stress-, hypoxia-, and apoptosis-related genes.

Contributed by Paula Hochman

(1) Schlenker R (2) Schwalie PC (3) Dettling S (4) Huesser T (5) Irmisch A (6) Mariani M (7) Martínez Gómez JM (8) Ribeiro A (9) Limani F (10) Herter S (11) Yángüez E (12) Hoves S (13) Somandin J (14) Siebourg-Polster J (15) Kam-Thong T (16) de Matos IG (17) Umana P (18) Dummer R (19) Levesque MP (20) Bacac M

Med

Using scRNAseq, Schlenker and Schwalie et al. analyzed peripheral blood cells and cells infiltrating tumors surgically resected from 22 patients with stage III–IV metastatic melanoma who subsequently received CPI therapy. CPI responders exhibited high levels of circulating classical and tumor-infiltrating monocytes, which preferentially transitioned to M1-like macrophages in tumors. In CPI responders, myeloid–T/NK cell interactions were proinflammatory and supported T cell priming and effector activities. In CPI non-responders, myeloid–T/NK cell interactions were immunosuppressive, and CD8+ TILs tended to express stress-, hypoxia-, and apoptosis-related genes.

Contributed by Paula Hochman

BACKGROUND: The treatment of melanoma, the deadliest form of skin cancer, has greatly benefited from immunotherapy. However, many patients do not show a durable response, which is only partially explained by known resistance mechanisms. METHODS: We performed single-cell RNA sequencing of tumor immune infiltrates and matched peripheral blood mononuclear cells of 22 checkpoint inhibitor (CPI)-naive stage III-IV metastatic melanoma patients. After sample collection, the same patients received CPI treatment, and their response was assessed. FINDINGS: CPI responders showed high levels of classical monocytes in peripheral blood, which preferentially transitioned toward CXCL9-expressing macrophages in tumors. Trajectories of tumor-infiltrating CD8(+) T cells diverged at the level of effector memory/stem-like T cells, with non-responder cells progressing into a state characterized by cellular stress and apoptosis-related gene expression. Consistently, predicted non-responder-enriched myeloid-T/natural killer cell interactions were primarily immunosuppressive, while responder-enriched interactions were supportive of T cell priming and effector function. CONCLUSIONS: Our study illustrates that the tumor immune microenvironment prior to CPI treatment can be indicative of response. In perspective, modulating the myeloid and/or effector cell compartment by altering the described cell interactions and transitions could improve immunotherapy response. FUNDING: This research was funded by Roche Pharma Research and Early Development.

Author Info: (1) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. Electronic address: ramona.schlenker@roche.com. (2) Roche Innovation Cent

Author Info: (1) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. Electronic address: ramona.schlenker@roche.com. (2) Roche Innovation Center Basel, pRED, Basel, Switzerland. Electronic address: petra.schwalie@roche.com. (3) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (4) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (5) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (6) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (7) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (8) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (9) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (10) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (11) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (12) Roche Innovation Center Munich, Roche Pharma Research and Early Development (pRED), Penzberg, Germany. (13) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (14) Roche Innovation Center Basel, pRED, Basel, Switzerland. (15) Roche Innovation Center Basel, pRED, Basel, Switzerland. (16) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (17) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland. (18) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (19) Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. (20) Roche Innovation Center Zurich, pRED, Schlieren, Switzerland.

Citation: Med 2024 Apr 4 Epub04/04/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38593812

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Control of adaptive immunity by pattern recognition receptors

(1) Carroll SL (2) Pasare C (3) Barton GM

Immunity

(1) Carroll SL (2) Pasare C (3) Barton GM

Immunity

One of the most significant conceptual advances in immunology in recent history is the recognition that signals from the innate immune system are required for induction of adaptive immune responses. Two breakthroughs were critical in establishing this paradigm: the identification of dendritic cells (DCs) as the cellular link between innate and adaptive immunity and the discovery of pattern recognition receptors (PRRs) as a molecular link that controls innate immune activation as well as DC function. Here, we recount the key events leading to these discoveries and discuss our current understanding of how PRRs shape adaptive immune responses, both indirectly through control of DC function and directly through control of lymphocyte function. In this context, we provide a conceptual framework for how variation in the signals generated by PRR activation, in DCs or other cell types, can influence T cell differentiation and shape the ensuing adaptive immune response.

Author Info: (1) Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA. (2) Division of Immunobiology and C

Author Info: (1) Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA. (2) Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH USA. (3) Division of Immunology & Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA USA; Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA 94720 USA. Electronic address: barton@berkeley.edu.

Citation: Immunity 2024 Apr 9 57:632-648 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38599163

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Pembrolizumab plus chemotherapy for first-line treatment of advanced triple-negative breast cancer

(1) Haiderali A (2) Huang M (3) Pan W (4) Akers KG (5) Maciel D (6) Frederickson AM

Future oncology

(1) Haiderali A (2) Huang M (3) Pan W (4) Akers KG (5) Maciel D (6) Frederickson AM

Future oncology

Aim: A systematic review and network meta-analysis (NMA) was performed to evaluate the efficacy of first-line treatments for locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) patients. Materials & methods: Databases were searched for randomized controlled trials evaluating first-line treatments for locally recurrent unresectable or metastatic TNBC patients. NMA was performed to estimate relative treatment effects on overall and progression-free survival between pembrolizumab + chemotherapy and other interventions. Results: NMA including eight trials showed that the relative efficacy of pembrolizumab + chemotherapy was statistically superior to that of other immunotherapy- or chemotherapy-based treatment regimens. Conclusion: Pembrolizumab + chemotherapy confers benefits in survival outcomes versus alternative interventions for the first-line treatment of locally recurrent unresectable or metastatic TNBC patients.

Author Info: (1) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (2) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 0706

Author Info: (1) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (2) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (3) Center for Observational & Real-World Evidence; Merck & Co., Inc., Rahway, NJ 07065, USA. (4) PRECISIONheor; New York, NY 11203, USA. (5) PRECISIONheor; New York, NY 11203, USA. (6) PRECISIONheor; New York, NY 11203, USA.

Citation: Future Oncol 2024 Apr 10 Epub04/10/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38597713

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Binimetinib in combination with nivolumab or nivolumab and ipilimumab in patients with previously treated microsatellite-stable metastatic colorectal cancer with RAS mutations in an open-label phase 1b/2 study

(1) Elez E (2) Cubillo A (3) Alfonso PG (4) Middleton MR (5) Chau I (6) Alkuzweny B (7) Alcasid A (8) Zhang X (9) Van Cutsem E

BMC cancer

(1) Elez E (2) Cubillo A (3) Alfonso PG (4) Middleton MR (5) Chau I (6) Alkuzweny B (7) Alcasid A (8) Zhang X (9) Van Cutsem E

BMC cancer

BACKGROUND: In patients with previously treated RAS-mutated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), a multicenter open-label phase 1b/2 trial was conducted to define the safety and efficacy of the MEK1/MEK2 inhibitor binimetinib in combination with the immune checkpoint inhibitor (ICI) nivolumab (anti-PD-1) or nivolumab and another ICI, ipilimumab (anti-CTLA4). METHODS: In phase 1b, participants were randomly assigned to Arm 1A (binimetinib 45 mg twice daily [BID] plus nivolumab 480 mg once every 4 weeks [Q4W]) or Arm 1B (binimetinib 45 mg BID plus nivolumab 480 mg Q4W and ipilimumab 1 mg/kg once every 8 weeks [Q8W]) to determine the maximum tolerable dose (MTD) and recommended phase 2 dose (RP2D) of binimetinib. The MTD/RP2D was defined as the highest dosage combination that did not cause medically unacceptable dose-limiting toxicities in more than 35% of treated participants in Cycle 1. During phase 2, participants were randomly assigned to Arm 2A (binimetinib MTD/RP2D plus nivolumab) or Arm 2B (binimetinib MTD/RP2D plus nivolumab and ipilimumab) to assess the safety and clinical activity of these combinations. RESULTS: In phase 1b, 21 participants were randomized to Arm 1A or Arm 1B; during phase 2, 54 participants were randomized to Arm 2A or Arm 2B. The binimetinib MTD/RP2D was determined to be 45 mg BID. In phase 2, no participants receiving binimetinib plus nivolumab achieved a response. Of the 27 participants receiving binimetinib, nivolumab, and ipilimumab, the overall response rate was 7.4% (90% CI: 1.3, 21.5). Out of 75 participants overall, 74 (98.7%) reported treatment-related adverse events (AEs), of whom 17 (22.7%) reported treatment-related serious AEs. CONCLUSIONS: The RP2D binimetinib regimen had a safety profile similar to previous binimetinib studies or nivolumab and ipilimumab combination studies. There was a lack of clinical benefit with either drug combination. Therefore, these data do not support further development of binimetinib in combination with nivolumab or nivolumab and ipilimumab in RAS-mutated MSS mCRC. TRIAL REGISTRATION: NCT03271047 (09/01/2017).

Author Info: (1) Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Aut˜noma de Barcelona, Barcelona, Spain. meelez@vhio.net. (2

Author Info: (1) Medical Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Universitat Aut˜noma de Barcelona, Barcelona, Spain. meelez@vhio.net. (2) Centro Integral, Oncol—gico Clara Campal, HM CIOCC, Madrid, Spain. Facultad HM Hospitales de Ciencias de La Salud UCJC, 28050, Madrid, Spain. (3) Medical Oncology Service, Hospital General Universitario Gregorio Mara–—n, Instituto de Investigaci—n Sanitaria Gregorio Mara–—n (IiSGM), Universidad Complutense, Madrid, Spain. (4) Department of Oncology, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK. (5) Gastrointestinal Unit, Royal Marsden Hospital, London & Surrey, UK. (6) Formerly Pfizer, Inc, San Diego, CA, USA. (7) Pfizer Inc, Collegeville, PA, USA. (8) Pfizer, Inc, New York, NY, USA. (9) University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium.

Citation: BMC Cancer 2024 Apr 11 24:446 Epub04/11/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38600471

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The role of the immunosuppressive PD-1/PD-L1 checkpoint pathway in the aging process and age-related diseases

(1) Salminen A

Journal of molecular medicine

(1) Salminen A

Journal of molecular medicine

The accumulation of senescent cells within tissues is a hallmark of the aging process. Senescent cells are also commonly present in many age-related diseases and in the cancer microenvironment. The escape of abnormal cells from immune surveillance indicates that there is some defect in the function of cytotoxic immune cells, e.g., CD8(+) T cells and natural killer (NK) cells. Recent studies have revealed that the expression of programmed death-ligand 1 (PD-L1) protein is abundantly increased in senescent cells. An increase in the amount of PD-L1 protein protects senescent cells from clearance by the PD-1 checkpoint receptor in cytotoxic immune cells. In fact, the activation of the PD-1 receptor suppresses the cytotoxic properties of CD8(+) T and NK cells, promoting a state of immunosenescence. The inhibitory PD-1/PD-L1 checkpoint pathway acts in cooperation with immunosuppressive cells; for example, activation of PD-1 receptor can enhance the differentiation of regulatory T cells (Treg), myeloid-derived suppressor cells (MDSC), and M2 macrophages, whereas the cytokines secreted by immunosuppressive cells stimulate the expression of the immunosuppressive PD-L1 protein. Interestingly, many signaling pathways known to promote cellular senescence and the aging process are crucial stimulators of the expression of PD-L1 protein, e.g., epigenetic regulation, inflammatory mediators, mTOR-related signaling, cGAS-STING pathway, and AhR signaling. It seems that the inhibitory PD-1/PD-L1 immune checkpoint axis has a crucial role in the accumulation of senescent cells and thus it promotes the aging process in tissues. Thus, the blockade of the PD-1/PD-L1 checkpoint signaling might be a potential anti-aging senolytic therapy. KEY MESSAGES: Senescent cells accumulate within tissues during aging and age-related diseases. Senescent cells are able to escape immune surveillance by cytotoxic immune cells. Expression of programmed death-ligand 1 (PD-L1) markedly increases in senescent cells. Age-related signaling stimulates the expression of PD-L1 protein in senescent cells. Inhibitory PD-1/PD-L1 checkpoint pathway suppresses clearance of senescent cells.

Author Info: (1) Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. antero.salminen@uef.fi.

Author Info: (1) Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211, Kuopio, Finland. antero.salminen@uef.fi.

Citation: J Mol Med (Berl) 2024 Apr 11 Epub04/11/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38600305

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A pan-cancer analysis of the microbiome in metastatic cancer

(1) Battaglia TW (2) Mimpen IL (3) Traets JJH (4) van Hoeck A (5) Zeverijn LJ (6) Geurts BS (7) de Wit GF (8) No‘ M (9) Hofland I (10) Vos JL (11) Cornelissen S (12) Alkemade M (13) Broeks A (14) Zuur CL (15) Cuppen E (16) Wessels L (17) van de Haar J (18) Voest E

Cell

(1) Battaglia TW (2) Mimpen IL (3) Traets JJH (4) van Hoeck A (5) Zeverijn LJ (6) Geurts BS (7) de Wit GF (8) No‘ M (9) Hofland I (10) Vos JL (11) Cornelissen S (12) Alkemade M (13) Broeks A (14) Zuur CL (15) Cuppen E (16) Wessels L (17) van de Haar J (18) Voest E

Cell

Microbial communities are resident to multiple niches of the human body and are important modulators of the host immune system and responses to anticancer therapies. Recent studies have shown that complex microbial communities are present within primary tumors. To investigate the presence and relevance of the microbiome in metastases, we integrated mapping and assembly-based metagenomics, genomics, transcriptomics, and clinical data of 4,160 metastatic tumor biopsies. We identified organ-specific tropisms of microbes, enrichments of anaerobic bacteria in hypoxic tumors, associations between microbial diversity and tumor-infiltrating neutrophils, and the association of Fusobacterium with resistance to immune checkpoint blockade (ICB) in lung cancer. Furthermore, longitudinal tumor sampling revealed temporal evolution of the microbial communities and identified bacteria depleted upon ICB. Together, we generated a pan-cancer resource of the metastatic tumor microbiome that may contribute to advancing treatment strategies.

Author Info: (1) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Division of Molecular Carcinogenesis, the Netherlands Cancer

Author Info: (1) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (2) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (3) Division of Tumor Biology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (4) Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Department of Head and Neck Surgery and Oncology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands. (5) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (6) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (7) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (8) Department of Pathology, Antoni van Leeuwenhoek/the Netherlands Cancer Institute, Amsterdam, the Netherlands. (9) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (10) Division of Tumor Biology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Head and Neck Service and Immunogenomic Oncology Platform, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (12) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (13) Core Facility Molecular Pathology & Biobanking, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (14) Division of Tumor Biology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Department of Head and Neck Surgery and Oncology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands; Department of Otorhinolaryngology Head and Neck Surgery, Leiden University Medical Center, Leiden, the Netherlands. (15) Center for Molecular Medicine, University Medical Centre Utrecht, Utrecht 3584CX, the Netherlands; Hartwig Medical Foundation, Science Park, Amsterdam 1098XH, the Netherlands. (16) Division of Molecular Carcinogenesis, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Faculty of EEMCS, Delft University of Technology, Delft 2628 CD, the Netherlands. (17) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. (18) Division of Molecular Oncology & Immunology, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands; Oncode Institute, the Netherlands Cancer Institute, Amsterdam 1066 CX, the Netherlands. Electronic address: e.voest@nki.nl.

Citation: Cell 2024 Apr 5 Epub04/05/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38599211

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Vaccine adjuvants: Tailoring innate recognition to send the right message

(1) Lavelle EC (2) McEntee CP

Immunity

(1) Lavelle EC (2) McEntee CP

Immunity

Adjuvants play pivotal roles in vaccine development, enhancing immunization efficacy through prolonged retention and sustained release of antigen, lymph node targeting, and regulation of dendritic cell activation. Adjuvant-induced activation of innate immunity is achieved via diverse mechanisms: for example, adjuvants can serve as direct ligands for pathogen recognition receptors or as inducers of cell stress and death, leading to the release of immunostimulatory-damage-associated molecular patterns. Adjuvant systems increasingly stimulate multiple innate pathways to induce greater potency. Increased understanding of the principles dictating adjuvant-induced innate immunity will subsequently lead to programming specific types of adaptive immune responses. This tailored optimization is fundamental to next-generation vaccines capable of inducing robust and sustained adaptive immune memory across different cohorts.

Author Info: (1) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. Electronic address: lavellee@tcd.ie. (2) School of Bioche

Author Info: (1) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland. Electronic address: lavellee@tcd.ie. (2) School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

Citation: Immunity 2024 Apr 9 57:772-789 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38599170

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Myeloid C-type lectin receptors in innate immune recognition

(1) Reis E Sousa C (2) Yamasaki S (3) Brown GD

Immunity

(1) Reis E Sousa C (2) Yamasaki S (3) Brown GD

Immunity

C-type lectin receptors (CLRs) expressed by myeloid cells constitute a versatile family of receptors that play a key role in innate immune recognition. Myeloid CLRs exhibit a remarkable ability to recognize an extensive array of ligands, from carbohydrates and beyond, and encompass pattern-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and markers of altered self. These receptors, classified into distinct subgroups, play pivotal roles in immune recognition and modulation of immune responses. Their intricate signaling pathways orchestrate a spectrum of cellular responses, influencing processes such as phagocytosis, cytokine production, and antigen presentation. Beyond their contributions to host defense in viral, bacterial, fungal, and parasitic infections, myeloid CLRs have been implicated in non-infectious diseases such as cancer, allergies, and autoimmunity. A nuanced understanding of myeloid CLR interactions with endogenous and microbial triggers is starting to uncover the context-dependent nature of their roles in innate immunity, with implications for therapeutic intervention.

Author Info: (1) Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK. Electronic address: caetano@crick.ac.uk. (2) Molecular Immunology, Research Institute

Author Info: (1) Immunobiology Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK. Electronic address: caetano@crick.ac.uk. (2) Molecular Immunology, Research Institute for Microbial Diseases, Immunology Frontier Research Center (IFReC), Osaka University, Suita 565-0871, Japan. Electronic address: yamasaki@biken.osaka-u.ac.jp. (3) MRC Centre for Medical Mycology at the University of Exeter, Geoffrey Pope Building, Stocker Road, Exeter EX4 4QD, UK. Electronic address: gordon.brown@exeter.ac.uk.

Citation: Immunity 2024 Apr 9 57:700-717 Epub

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38599166

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Bispecific antibodies tethering innate receptors induce human tolerant-dendritic cells and regulatory T cells

(1) Lamendour L (2) Gilotin M (3) Deluce-Kakwata Nkor N (4) Lakhrif Z (5) Meley D (6) Poupon A (7) Laboute T (8) di Tommaso A (9) Pin JJ (10) Mulleman D (11) Le MŽlŽdo G (12) Aubrey N (13) Watier H (14) Velge-Roussel F

Frontiers in immunology | Free PMC Article

(1) Lamendour L (2) Gilotin M (3) Deluce-Kakwata Nkor N (4) Lakhrif Z (5) Meley D (6) Poupon A (7) Laboute T (8) di Tommaso A (9) Pin JJ (10) Mulleman D (11) Le MŽlŽdo G (12) Aubrey N (13) Watier H (14) Velge-Roussel F

Frontiers in immunology | Free PMC Article

There is an urgent need for alternative therapies targeting human dendritic cells (DCs) that could reverse inflammatory syndromes in many autoimmune and inflammatory diseases and organ transplantations. Here, we describe a bispecific antibody (bsAb) strategy tethering two pathogen-recognition receptors at the surface of human DCs. This cross-linking switches DCs into a tolerant profile able to induce regulatory T-cell differentiation. The bsAbs, not parental Abs, induced interleukin 10 and transforming growth factor _1 secretion in monocyte-derived DCs and human peripheral blood mononuclear cells. In addition, they induced interleukin 10 secretion by synovial fluid cells in rheumatoid arthritis and gout patients. This concept of bsAb-induced tethering of surface pathogen-recognition receptors switching cell properties opens a new therapeutic avenue for controlling inflammation and restoring immune tolerance.

Author Info: (1) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. (2) EA7501, Groupe Innovation

Author Info: (1) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. (2) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. (3) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. (4) Infectiologie et SantŽ Publique (ISP) UMR 1282, INRAE, Team BioMAP, UniversitŽ de Tours, Tours, France. (5) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. (6) institut de recherche pour l'agriculture, l'alimentation et 'environnement (INRAE) UMR 0085, centre de recherche scientifique (CNRS) UMR 7247, Physiologie de la Reproduction et des Comportements, UniversitŽ de Tours, Tours, France. MAbSilico, Tours, France. (7) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. (8) Infectiologie et SantŽ Publique (ISP) UMR 1282, INRAE, Team BioMAP, UniversitŽ de Tours, Tours, France. (9) Dendritics, Lyon, France. (10) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. Service de Rhumatologie, Centre Hospitalo-Universitaire (CHRU) de Tours, Tours, France. (11) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. Service de Rhumatologie, Centre Hospitalo-Universitaire (CHRU) de Tours, Tours, France. (12) Infectiologie et SantŽ Publique (ISP) UMR 1282, INRAE, Team BioMAP, UniversitŽ de Tours, Tours, France. (13) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France. (14) EA7501, Groupe Innovation et Ciblage Cellulaire, Team Fc RŽcepteurs, Anticorps et MicroEnvironnement (FRAME), UniversitŽ de Tours, Tours, France.

Citation: Front Immunol 2024 15:1369117 Epub03/26/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38601165

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