Journal Articles

Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma Spotlight 

(1) Rade M (2) Grieb N (3) Weiss R (4) Sia J (5) Fischer L (6) Born P (7) Boldt A (8) Fricke S (9) Franz P (10) Scolnick J (11) Venkatraman L (12) Xu S (13) Kloetzer C (14) Heyn S (15) Kubasch AS (16) Baber R (17) Wang SY (18) Bach E (19) Hoffmann S (20) Ussmann J (21) Schetschorke B (22) Hell S (23) Schwind S (24) Metzeler KH (25) Herling M (26) Jentzsch M (27) Franke GN (28) Sack U (29) Kšhl U (30) Platzbecker U (31) Reiche K (32) Vucinic V (33) Merz M

Nature cancer

To find markers of response and non-response to BCMA-targeted CAR T cell therapy, Rade and Grieb et al. applied longitudinal, single-cell multiomics on peripheral blood and bone marrow before and after CAR T cell infusion in heavily pretreated patients with relapsed/refractory MM. Differences between responders (5 CR) and non-responders (5 with poor outcomes) were identified at apheresis, prior to CAR T cell infusion. Non-responders had a suppressive microenvironment with increased CD39+ monocytes and fewer and functionally impaired CD8+ T cells and NK cells. After therapy, hyperexpanded CAR T cell clones had an exhausted PD-1+ phenotype compared to low/intermediate clones.

Contributed by Katherine Turner

(1) Rade M (2) Grieb N (3) Weiss R (4) Sia J (5) Fischer L (6) Born P (7) Boldt A (8) Fricke S (9) Franz P (10) Scolnick J (11) Venkatraman L (12) Xu S (13) Kloetzer C (14) Heyn S (15) Kubasch AS (16) Baber R (17) Wang SY (18) Bach E (19) Hoffmann S (20) Ussmann J (21) Schetschorke B (22) Hell S (23) Schwind S (24) Metzeler KH (25) Herling M (26) Jentzsch M (27) Franke GN (28) Sack U (29) Kšhl U (30) Platzbecker U (31) Reiche K (32) Vucinic V (33) Merz M

Nature cancer

To find markers of response and non-response to BCMA-targeted CAR T cell therapy, Rade and Grieb et al. applied longitudinal, single-cell multiomics on peripheral blood and bone marrow before and after CAR T cell infusion in heavily pretreated patients with relapsed/refractory MM. Differences between responders (5 CR) and non-responders (5 with poor outcomes) were identified at apheresis, prior to CAR T cell infusion. Non-responders had a suppressive microenvironment with increased CD39+ monocytes and fewer and functionally impaired CD8+ T cells and NK cells. After therapy, hyperexpanded CAR T cell clones had an exhausted PD-1+ phenotype compared to low/intermediate clones.

Contributed by Katherine Turner

ABSTRACT: Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8(+) T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma.

Author Info: (1) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. (2) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, L

Author Info: (1) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. (2) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. Innovation Center Computer Assisted Surgery, University Hospital of Leipzig, Leipzig, Germany. (3) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (4) Singleron Biotechnologies, Cologne, Germany. (5) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (6) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (7) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (8) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (9) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (10) Singleron Biotechnologies, Cologne, Germany. (11) Singleron Biotechnologies, Cologne, Germany. (12) Singleron Biotechnologies, Cologne, Germany. (13) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (14) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (15) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (16) Institute for Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany. Leipzig Medical Biobank, University Leipzig, Leipzig, Germany. (17) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (18) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (19) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (20) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (21) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (22) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (23) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (24) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (25) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (26) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (27) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (28) Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (29) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. (30) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (31) Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany. Institute for Clinical Immunology, University Hospital of Leipzig, Leipzig, Germany. Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Dresden, Leipzig, Germany. (32) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. (33) Department of Hematology, Cellular Therapy and Hemostaseology, University Hospital of Leipzig, Leipzig, Germany. maximilian.merz@medizin.uni-leipzig.de.

Citation: Nat Cancer 2024 Apr 19 Epub04/19/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38641734

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A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron

Spotlight 

(1) Sharma G (2) Sharma A (3) Kim I (4) Cha DG (5) Kim S (6) Park ES (7) Noh JG (8) Lee J (9) Ku JH (10) Choi YH (11) Kong J (12) Lee H (13) Ko H (14) Lee J (15) Notaro A (16) Hong SH (17) Rhee JH (18) Kim SG (19) De Castro C (20) Molinaro A (21) Shin K (22) Kim S (23) Kim JK (24) Rudra D (25) Im SH

Nature immunology

Sharma et al. identified the commensal LPIMB19 (LP) as a stimulator of CD8+ T cell responses, and verified its efficacy in multiple solid tumor models, including a human BLCA organoid model. The primary immunogenic effector was the capsular polysaccharide RHP, which endowed TILs with an effector-like cytotoxic phenotype and induced macrophage activation dependent on TLR2. Iron transport was upregulated in i.t. macrophages, promoting iron uptake (via LCN2 secretion), with concomitant depletion of iron in tumor cells and enhanced apoptosis. Both TLR2 and LCN2 were required for antitumor efficacy, suggesting a role for macrophage-mediated “nutritional immunity”.

Contributed by Morgan Janes

(1) Sharma G (2) Sharma A (3) Kim I (4) Cha DG (5) Kim S (6) Park ES (7) Noh JG (8) Lee J (9) Ku JH (10) Choi YH (11) Kong J (12) Lee H (13) Ko H (14) Lee J (15) Notaro A (16) Hong SH (17) Rhee JH (18) Kim SG (19) De Castro C (20) Molinaro A (21) Shin K (22) Kim S (23) Kim JK (24) Rudra D (25) Im SH

Nature immunology

Sharma et al. identified the commensal LPIMB19 (LP) as a stimulator of CD8+ T cell responses, and verified its efficacy in multiple solid tumor models, including a human BLCA organoid model. The primary immunogenic effector was the capsular polysaccharide RHP, which endowed TILs with an effector-like cytotoxic phenotype and induced macrophage activation dependent on TLR2. Iron transport was upregulated in i.t. macrophages, promoting iron uptake (via LCN2 secretion), with concomitant depletion of iron in tumor cells and enhanced apoptosis. Both TLR2 and LCN2 were required for antitumor efficacy, suggesting a role for macrophage-mediated “nutritional immunity”.

Contributed by Morgan Janes

ABSTRACT: Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus_plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8(+) T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.

Author Info: (1) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. ImmunoBiome, Bio Open Innovation Center, Pohang, Republic of Kore

Author Info: (1) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. ImmunoBiome, Bio Open Innovation Center, Pohang, Republic of Korea. (2) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. Innovation Research Center for Bio-future Technology (B-IRC), Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (3) ImmunoBiome, Bio Open Innovation Center, Pohang, Republic of Korea. (4) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea. (5) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (6) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea. (7) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (8) Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea. (9) Department of Urology, College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea. (10) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea. (11) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (12) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (13) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (14) ImmunoBiome, Bio Open Innovation Center, Pohang, Republic of Korea. (15) Department of Chemical Sciences, University of Napoli Federico II Complesso Universitario Monte Santangelo, Via Cintia 4, I-80126, Naples, Italy. (16) Clinical Vaccine R&D Center and Combinatorial Tumor Immunotherapy MRC, Chonnam National University, Hwasun-gun, Republic of Korea. (17) Clinical Vaccine R&D Center and Combinatorial Tumor Immunotherapy MRC, Chonnam National University, Hwasun-gun, Republic of Korea. (18) College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University, Seoul, Republic of Korea. (19) Department of Chemical Sciences, University of Napoli Federico II Complesso Universitario Monte Santangelo, Via Cintia 4, I-80126, Naples, Italy. (20) Department of Chemical Sciences, University of Napoli Federico II Complesso Universitario Monte Santangelo, Via Cintia 4, I-80126, Naples, Italy. (21) Institute of Molecular Biology and Genetics, Seoul National University, Seoul, Republic of Korea. Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea. (22) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. (23) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea. (24) ImmunoBiome, Bio Open Innovation Center, Pohang, Republic of Korea. drudra@shanghaitech.edu.cn. School of Life Science and Technology, ShanghaiTech University, Shanghai, China. drudra@shanghaitech.edu.cn. (25) Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea. iimsh@postech.ac.kr. ImmunoBiome, Bio Open Innovation Center, Pohang, Republic of Korea. iimsh@postech.ac.kr. Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Republic of Korea. iimsh@postech.ac.kr.

Citation: Nat Immunol 2024 May 25:790-801 Epub04/25/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38664585

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Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

Spotlight 

(1) Hu Y (2) Sarkar A (3) Song K (4) Michael S (5) Hook M (6) Wang R (7) Heczey A (8) Song X

Cell reports. Medicine

To support CAR T cell metabolism and functionality in the tumor microenvironment, Hu and Sarkar et al. developed “metabolically refueled” CAR T cells (MR-CAR-T) expressing CD26, a T cell costimulatory molecule, and ADA1, an enzyme that generates inosine as an alternative T cell energy source. ADA1 was fused to an anti-CD3 scFv to both activate and direct ADA1 to T cells. Compared to standard CAR T cells, MR-CAR-T improved in vitro migration, cytotoxicity, and proliferation; in vivo, MR-CAR-T increased tumor inosine concentration and T cell infiltration, leading to superior tumor control in HER2- or GPC3-expressing tumor models.

Contributed by Alex Najibi

(1) Hu Y (2) Sarkar A (3) Song K (4) Michael S (5) Hook M (6) Wang R (7) Heczey A (8) Song X

Cell reports. Medicine

To support CAR T cell metabolism and functionality in the tumor microenvironment, Hu and Sarkar et al. developed “metabolically refueled” CAR T cells (MR-CAR-T) expressing CD26, a T cell costimulatory molecule, and ADA1, an enzyme that generates inosine as an alternative T cell energy source. ADA1 was fused to an anti-CD3 scFv to both activate and direct ADA1 to T cells. Compared to standard CAR T cells, MR-CAR-T improved in vitro migration, cytotoxicity, and proliferation; in vivo, MR-CAR-T increased tumor inosine concentration and T cell infiltration, leading to superior tumor control in HER2- or GPC3-expressing tumor models.

Contributed by Alex Najibi

ABSTRACT: Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor _1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor cell feeding. In mouse models of hepatocellular carcinoma and non-small cell lung cancer, metabolically refueled CAR T cells exhibit superior tumor reduction compared to unmodified CAR T cells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors.

Author Info: (1) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Bioscien

Author Info: (1) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA. (2) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA. (3) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA; Department of Biology, University of Houston, Houston, TX, USA. (4) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA; Department of Synthesis Biology, University of Houston, Houston, TX, USA. (5) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA. (6) Center for Childhood Cancer Research, Hematology/Oncology & BMT, Abigail Wexner Research Institute at Nationwide Children's Hospital, Department of Pediatrics at The Ohio State University, Columbus, OH, USA. (7) Texas Children's Hospital, Houston, TX, USA; Department of Pediatric, Baylor College of Medicine, Houston, TX, USA. (8) Department of Translational Medical Sciences, School of Medicine, Texas A&M University, Houston, TX, USA; Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA. Electronic address: xsong@tamu.edu.

Citation: Cell Rep Med 2024 Apr 22 101530 Epub04/22/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38688275

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Facile generation of biepitopic antibodies with intrinsic agonism for activating receptors in the tumor necrosis factor superfamily Spotlight 

(1) Jhajj HS (2) Schardt JS (3) Khalasawi N (4) Yao EL (5) Lwo TS (6) Kwon NY (7) O'Meara RL (8) Desai AA (9) Tessier PM

bioRxiv | Free PMC Article

Jhajj, Schardt, and Khalasawi et al. report a systematic method for discovering single-chain antibodies with unique epitopes (relative to clinical-stage antibodies) targeting TNF receptors, which were then fused to the light chains of the clinical-stage IgGs to generate human biepitopic agonist antibodies, eliminating the need for animal immunization, humanization, and molecular reformatting. Biepitopic OX40 antibodies showed potent, FcγR-independent primary human CD4+ T cell activation. The competition-based antibody screening platform was generalizable to other members of the TNF receptor superfamily (CD137; 41-BB).

Contributed by Shishir Pant

(1) Jhajj HS (2) Schardt JS (3) Khalasawi N (4) Yao EL (5) Lwo TS (6) Kwon NY (7) O'Meara RL (8) Desai AA (9) Tessier PM

bioRxiv | Free PMC Article

Jhajj, Schardt, and Khalasawi et al. report a systematic method for discovering single-chain antibodies with unique epitopes (relative to clinical-stage antibodies) targeting TNF receptors, which were then fused to the light chains of the clinical-stage IgGs to generate human biepitopic agonist antibodies, eliminating the need for animal immunization, humanization, and molecular reformatting. Biepitopic OX40 antibodies showed potent, FcγR-independent primary human CD4+ T cell activation. The competition-based antibody screening platform was generalizable to other members of the TNF receptor superfamily (CD137; 41-BB).

Contributed by Shishir Pant

ABSTRACT: Agonist antibodies that activate cellular receptors are being pursued for therapeutic applications ranging from neurodegenerative diseases to cancer. For the tumor necrosis factor (TNF) receptor superfamily, higher-order clustering of three or more receptors is key to their potent activation. This can be achieved using antibodies that recognize two unique epitopes on the same receptor and mediate receptor superclustering. However, identifying compatible pairs of antibodies to generate biepitopic antibodies (also known as biparatopic antibodies) for activating TNF receptors typically requires animal immunization and is a laborious and unpredictable process. Here, we report a simple method for systematically identifying biepitopic antibodies that potently activate TNF receptors without the need for additional animal immunization. Our approach uses off-the-shelf, receptor-specific IgG antibodies, which lack intrinsic (Fc-gamma receptor-independent) agonist activity, to first block their corresponding epitopes. Next, we perform selections for single-chain antibodies from human nonimmune libraries that bind accessible epitopes on the same ectodomains using yeast surface display and fluorescence-activated cell sorting. The selected single-chain antibodies are finally fused to the light chains of IgGs to generate human tetravalent antibodies that engage two different receptor epitopes and mediate potent receptor activation. We highlight the broad utility of this approach by converting several existing clinical-stage antibodies against TNF receptors, including ivuxolimab and pogalizumab against OX40 and utomilumab against CD137, into biepitopic antibodies with highly potent agonist activity. We expect that this widely accessible methodology can be used to systematically generate biepitopic antibodies for activating other receptors in the TNF receptor superfamily and many other receptors whose activation is dependent on strong receptor clustering.

Author Info: (1) Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (2) Departmen

Author Info: (1) Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (2) Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (3) Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (4) Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (5) Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (6) Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (7) Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (8) Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA. (9) Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA. Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Citation: bioRxiv 2023 Dec 12 Epub12/12/2023

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38168220

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Next-generation anti-PD-L1/IL-15 immunocytokine elicits superior antitumor immunity in cold tumors with minimal toxicity

(1) Shi W (2) Liu N (3) Liu Z (4) Yang Y (5) Zeng Q (6) Wang Y (7) Song L (8) Hu F (9) Fu J (10) Chen J (11) Wu M (12) Zhou L (13) Zhu F (14) Gong L (15) Zhu J (16) Jiang L (17) Lu H

Cell reports. Medicine

(1) Shi W (2) Liu N (3) Liu Z (4) Yang Y (5) Zeng Q (6) Wang Y (7) Song L (8) Hu F (9) Fu J (10) Chen J (11) Wu M (12) Zhou L (13) Zhu F (14) Gong L (15) Zhu J (16) Jiang L (17) Lu H

Cell reports. Medicine

The clinical applications of immunocytokines are severely restricted by dose-limiting toxicities. To address this challenge, here we propose a next-generation immunocytokine concept involving the design of LH05, a tumor-conditional anti-PD-L1/interleukin-15 (IL-15) prodrug. LH05 innovatively masks IL-15 with steric hindrance, mitigating the "cytokine sink" effect of IL-15 and reducing systemic toxicities associated with wild-type anti-PD-L1/IL-15. Moreover, upon specific proteolytic cleavage within the tumor microenvironment, LH05 releases an active IL-15 superagonist, exerting potent antitumor effects. Mechanistically, the antitumor efficacy of LH05 depends on the increased infiltration of CD8(+) T and natural killer cells by stimulating the chemokines CXCL9 and CXCL10, thereby converting cold tumors into hot tumors. Additionally, the tumor-conditional anti-PD-L1/IL-15 can synergize with an oncolytic virus or checkpoint blockade in advanced and metastatic tumor models. Our findings provide a compelling proof of concept for the development of next-generation immunocytokines, contributing significantly to current knowledge and strategies of immunotherapy.

Author Info: (1) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong Unive

Author Info: (1) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (2) Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. (3) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (4) Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. (5) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (6) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (7) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (8) Hangzhou Converd Inc., Hangzhou, Zhejiang 311121, China. (9) Hangzhou Converd Inc., Hangzhou, Zhejiang 311121, China. (10) Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (11) Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (12) Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200023, China. (13) Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200052, China. (14) Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; School of Pharmacy, University of Chinese Academy of Sciences, Beijing 100049, China. (15) Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. (16) Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: jiang_long@shsmu.edu.cn. (17) Shanghai Frontiers Science Center for Drug Target Identification and Delivery, National Key Laboratory of Innovative Immunotherapy, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China; Engineering Research Center of Cell & Therapeutic Antibody, Ministry of Education, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China. Electronic address: roadeer@sjtu.edu.cn.

Citation: Cell Rep Med 2024 Apr 25 101531 Epub04/25/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38697105

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A blueprint for tumor-infiltrating B cells across human cancers

(1) Ma J (2) Wu Y (3) Ma L (4) Yang X (5) Zhang T (6) Song G (7) Li T (8) Gao K (9) Shen X (10) Lin J (11) Chen Y (12) Liu X (13) Fu Y (14) Gu X (15) Chen Z (16) Jiang S (17) Rao D (18) Pan J (19) Zhang S (20) Zhou J (21) Huang C (22) Shi S (23) Fan J (24) Guo G (25) Zhang X (26) Gao Q

Science

(1) Ma J (2) Wu Y (3) Ma L (4) Yang X (5) Zhang T (6) Song G (7) Li T (8) Gao K (9) Shen X (10) Lin J (11) Chen Y (12) Liu X (13) Fu Y (14) Gu X (15) Chen Z (16) Jiang S (17) Rao D (18) Pan J (19) Zhang S (20) Zhou J (21) Huang C (22) Shi S (23) Fan J (24) Guo G (25) Zhang X (26) Gao Q

Science

B lymphocytes are essential mediators of humoral immunity and play multiple roles in human cancer. To decode the functions of tumor-infiltrating B cells, we generated a B cell blueprint encompassing single-cell transcriptome, B cell-receptor repertoire, and chromatin accessibility data across 20 different cancer types (477 samples, 269 patients). B cells harbored extraordinary heterogeneity and comprised 15 subsets, which could be grouped into two independent developmental paths (extrafollicular versus germinal center). Tumor types grouped into the extrafollicular pathway were linked with worse clinical outcomes and resistance to immunotherapy. The dysfunctional extrafollicular program was associated with glutamine-derived metabolites through epigenetic-metabolic cross-talk, which promoted a T cell-driven immunosuppressive program. These data suggest an intratumor B cell balance between extrafollicular and germinal-center responses and suggest that humoral immunity could possibly be harnessed for B cell-targeting immunotherapy.

Author Info: (1) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, F

Author Info: (1) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (2) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (3) Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, and Stem Cell Institute, Zhejiang University, Hangzhou 310058, China. (4) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (5) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (6) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (7) The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. (8) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (9) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (10) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (11) The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. (12) The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. (13) Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, and Stem Cell Institute, Zhejiang University, Hangzhou 310058, China. (14) The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. (15) The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. (16) The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. (17) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (18) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (19) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (20) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (21) Department of Gastrointestinal Surgery, Shanghai General Hospital Affiliated to Shanghai Jiaotong University, Shanghai 200080, China. (22) Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China. (23) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China. (24) Center for Stem Cell and Regenerative Medicine, Zhejiang University School of Medicine, and Stem Cell Institute, Zhejiang University, Hangzhou 310058, China. (25) The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai 200031, China. (26) Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Citation: Science 2024 May 3 384:eadj4857 Epub05/03/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38696569

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Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence

(1) Cappabianca D (2) Pham D (3) Forsberg MH (4) Bugel M (5) Tommasi A (6) Lauer A (7) Vidugiriene J (8) Hrdlicka B (9) McHale A (10) Sodji QH (11) Skala MC (12) Capitini CM (13) Saha K

Molecular therapy. Methods & clinical development | Free PMC Article

(1) Cappabianca D (2) Pham D (3) Forsberg MH (4) Bugel M (5) Tommasi A (6) Lauer A (7) Vidugiriene J (8) Hrdlicka B (9) McHale A (10) Sodji QH (11) Skala MC (12) Capitini CM (13) Saha K

Molecular therapy. Methods & clinical development | Free PMC Article

Manufacturing chimeric antigen receptor (CAR) T cell therapies is complex, with limited understanding of how medium composition impacts T cell phenotypes. CRISPR-Cas9 ribonucleoproteins can precisely insert a CAR sequence while disrupting the endogenous T cell receptor alpha constant (TRAC) gene resulting in TRAC-CAR T cells with an enriched stem cell memory T cell population, a process that could be further optimized through modifications to the medium composition. In this study we generated anti-GD2 TRAC-CAR T cells using "metabolic priming" (MP), where the cells were activated in glucose/glutamine-low medium and then expanded in glucose/glutamine-high medium. T cell products were evaluated using spectral flow cytometry, metabolic assays, cytokine production, cytotoxicity assays in vitro, and potency against human GD2+ xenograft neuroblastoma models in vivo. Compared with standard TRAC-CAR T cells, MP TRAC-CAR T cells showed less glycolysis, higher CCR7/CD62L expression, more bound NAD(P)H activity, and reduced IFN-_, IL-2, IP-10, IL-1_, IL-17, and TGF-_ production at the end of manufacturing ex vivo, with increased central memory CAR T cells and better persistence observed in vivo. MP with medium during CAR T cell biomanufacturing can minimize glycolysis and enrich memory phenotypes ex vivo, which could lead to better responses against solid tumors in vivo.

Author Info: (1) Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 5

Author Info: (1) Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. (2) Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI 53715, USA. (3) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (4) Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. (5) Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. (6) Promega Corporation, Fitchburg, WI 53711, USA. (7) Promega Corporation, Fitchburg, WI 53711, USA. (8) Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. (9) Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. (10) University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. (11) Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. Morgridge Institute for Research, University of Wisconsin-Madison, Madison, WI 53715, USA. University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA. (12) Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, USA. University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA. (13) Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA. Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53715, USA. University of Wisconsin Carbone Cancer Center, University of Wisconsin-Madison, Madison, WI 53705, USA.

Citation: Mol Ther Methods Clin Dev 2024 Jun 13 32:101249 Epub04/10/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38699288

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Patient-derived follicular lymphoma spheroids recapitulate lymph node signaling and immune profile uncovering galectin-9 as a novel immunotherapeutic target

(1) Doba–o-L—pez C (2) Valero JG (3) Araujo-Ayala F (4) Nadeu F (5) Gava F (6) Faria C (7) Norlund M (8) Morin R (9) Bernes-Lasserre P (10) Arenas F (11) Grau M (12) L—pez C (13) L—pez-Oreja I (14) Serrat N (15) Mart’nez-Farran A (16) Hern‡ndez L (17) Playa-Albinyana H (18) GimŽnez R (19) Beˆ S (20) Campo E (21) Lagarde JM (22) L—pez-Guillermo A (23) Magnano L (24) Colomer D (25) Bezombes C (26) PŽrez-Gal‡n P

Blood cancer journal

(1) Doba–o-L—pez C (2) Valero JG (3) Araujo-Ayala F (4) Nadeu F (5) Gava F (6) Faria C (7) Norlund M (8) Morin R (9) Bernes-Lasserre P (10) Arenas F (11) Grau M (12) L—pez C (13) L—pez-Oreja I (14) Serrat N (15) Mart’nez-Farran A (16) Hern‡ndez L (17) Playa-Albinyana H (18) GimŽnez R (19) Beˆ S (20) Campo E (21) Lagarde JM (22) L—pez-Guillermo A (23) Magnano L (24) Colomer D (25) Bezombes C (26) PŽrez-Gal‡n P

Blood cancer journal

Follicular lymphoma (FL), the most common indolent non-Hodgkin lymphoma, constitutes a paradigm of immune tumor microenvironment (TME) contribution to disease onset, progression, and heterogenous clinical outcome. Here we present the first FL-Patient Derived Lymphoma Spheroid (FL-PDLS), including fundamental immune actors and features of TME in FL lymph nodes (LNs). FL-PDLS is organized in disc-shaped 3D structures composed of proliferating B and T cells, together with macrophages with an intermediate M1/M2 phenotype. FL-PDLS recapitulates the most relevant B-cell transcriptional pathways present in FL-LN (proliferation, epigenetic regulation, mTOR, adaptive immune system, among others). The T cell compartment in the FL-PDLS preserves CD4 subsets (follicular helper, regulatory, and follicular regulatory), also encompassing the spectrum of activation/exhaustion phenotypes in CD4 and CD8 populations. Moreover, this system is suitable for chemo and immunotherapy testing, recapitulating results obtained in the clinic. FL-PDLS allowed uncovering that soluble galectin-9 limits rituximab, rituximab, plus nivolumab/TIM-3 antitumoral activities. Blocking galectin-9 improves rituximab efficacy, highlighting galectin-9 as a novel immunotherapeutic target in FL. In conclusion, FL-PDLS maintains the crosstalk between malignant B cells and the immune LN-TME and constitutes a robust and multiplexed pre-clinical tool to perform drug screening in a patient-derived system, advancing toward personalized therapeutic approaches.

Author Info: (1) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC)

Author Info: (1) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (2) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (3) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (4) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (5) UniversitŽ de Toulouse, INSERM, CNRS, UniversitŽ de Toulouse III-Paul Sabatier, Centre de Recherches en CancŽrologie de Toulouse, Toulouse, France. (6) UniversitŽ de Toulouse, INSERM, CNRS, UniversitŽ de Toulouse III-Paul Sabatier, Centre de Recherches en CancŽrologie de Toulouse, Toulouse, France. (7) IMACTIV-3D, Toulouse, France. (8) IMACTIV-3D, Toulouse, France. (9) IMACTIV-3D, Toulouse, France. (10) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (11) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. (12) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. University of Barcelona, Medical School, Barcelona, Spain. (13) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. Secci— Hematopatologia, Servei d'Anatomia Patol˜gica, Hospital Cl’nic, Barcelona, Spain. (14) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. (15) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. (16) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (17) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (18) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. (19) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. University of Barcelona, Medical School, Barcelona, Spain. Secci— Hematopatologia, Servei d'Anatomia Patol˜gica, Hospital Cl’nic, Barcelona, Spain. (20) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. University of Barcelona, Medical School, Barcelona, Spain. Secci— Hematopatologia, Servei d'Anatomia Patol˜gica, Hospital Cl’nic, Barcelona, Spain. (21) IMACTIV-3D, Toulouse, France. (22) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. University of Barcelona, Medical School, Barcelona, Spain. Servei Hematologia, Hospital Cl’nic, Barcelona, Spain. (23) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. IMACTIV-3D, Toulouse, France. University of Barcelona, Medical School, Barcelona, Spain. Servei Hematologia, Hospital Cl’nic, Barcelona, Spain. (24) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. University of Barcelona, Medical School, Barcelona, Spain. Secci— Hematopatologia, Servei d'Anatomia Patol˜gica, Hospital Cl’nic, Barcelona, Spain. (25) UniversitŽ de Toulouse, INSERM, CNRS, UniversitŽ de Toulouse III-Paul Sabatier, Centre de Recherches en CancŽrologie de Toulouse, Toulouse, France. christine.bezombes@inserm.fr. (26) Fundaci— de Recerca Cl’nic Barcelona - Institut d'Investigacions Biomdiques August Pi i Sunyer, Barcelona, Spain. pperez@recerca.clinic.cat. Centro de Investigaci—n BiomŽdica en Red-Oncolog’a (CIBERONC), Madrid, Spain. pperez@recerca.clinic.cat.

Citation: Blood Cancer J 2024 May 2 14:75 Epub05/02/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38697976

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Targeting the dendritic cell-secreted immunoregulatory cytokine CCL22 alleviates radioresistance

(1) Bugno J (2) Wang L (3) Yu X (4) Cao X (5) Wang J (6) Huang X (7) Yang K (8) Piffko A (9) Chen K (10) Luo SY (11) Naccasha E (12) Hou Y (13) Fu S (14) He C (15) Fu YX (16) Liang HL (17) Weichselbaum RR

Clinical Cancer Research

(1) Bugno J (2) Wang L (3) Yu X (4) Cao X (5) Wang J (6) Huang X (7) Yang K (8) Piffko A (9) Chen K (10) Luo SY (11) Naccasha E (12) Hou Y (13) Fu S (14) He C (15) Fu YX (16) Liang HL (17) Weichselbaum RR

Clinical Cancer Research

PURPOSE: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that dendritic cells (cDC) maintain Treg we sought to identify and target cDC signaling to block Treg infiltration after radiation. EXPERIMENTAL DESIGN: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT, but associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (_EGFR-IFN_) was examined to block Treg infiltration and promote a CD8+ T cell response after RT. RESULTS: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. _EGFR-IFN_ blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration. CONCLUSIONS: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. _EGFR-IFN_ added to RT provided robust antitumor responses better than systemic free interferon administration, and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy.

Author Info: (1) University of Chicago, Chicago, United States. (2) University of Chicago, Chicago, IL, United States. (3) University of Chicago, Chicago, IL, United States. (4) Guangzhou Natio

Author Info: (1) University of Chicago, Chicago, United States. (2) University of Chicago, Chicago, IL, United States. (3) University of Chicago, Chicago, IL, United States. (4) Guangzhou National Laboratory, China. (5) University of Chicago, Chicago, IL, United States. (6) University of Chicago, Chicago, IL, United States. (7) University of Chicago, Chicago, IL, United States. (8) University of Chicago, Chicago, IL, United States. (9) University of Chicago, Chicago, United States. (10) University of Chicago, Chicago, United States. (11) University of Chicago, Chicago, IL, United States. (12) Xi'an Jiaotong University, Xi'an, Shaanxi, China. (13) The University of Texas Southwestern Medical Center, United States. (14) University of Chicago, Chicago, IL, United States. (15) Tsinghua University, beijing, China. (16) University of Chicago, Chicago, IL, United States. (17) University of Chicago, Chicago, IL, United States.

Citation: Clin Cancer Res 2024 May 1 Epub05/01/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38691100

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Tertiary lymphoid structures in cancer: maturation and induction

(1) Chen Y (2) Wu Y (3) Yan G (4) Zhang G

Frontiers in immunology | Free PMC Article

(1) Chen Y (2) Wu Y (3) Yan G (4) Zhang G

Frontiers in immunology | Free PMC Article

Tertiary lymphoid structure (TLS) is an ectopic lymphocyte aggregate formed in peripheral non-lymphoid tissues, including inflamed or cancerous tissue. Tumor-associated TLS serves as a prominent center of antigen presentation and adaptive immune activation within the periphery, which has exhibited positive prognostic value in various cancers. In recent years, the concept of maturity regarding TLS has been proposed and mature TLS, characterized by well-developed germinal centers, exhibits a more potent tumor-suppressive capacity with stronger significance. Meanwhile, more and more evidence showed that TLS can be induced by therapeutic interventions during cancer treatments. Thus, the evaluation of TLS maturity and the therapeutic interventions that induce its formation are critical issues in current TLS research. In this review, we aim to provide a comprehensive summary of the existing classifications for TLS maturity and therapeutic strategies capable of inducing its formation in tumors.

Author Info: (1) Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Skin Cancer Center, Shanghai Skin Disease Hospital, School o

Author Info: (1) Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Skin Cancer Center, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Institute of Photomedicine, School of Medicine, Tongji University, Shanghai, China. (2) Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Skin Cancer Center, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Institute of Photomedicine, School of Medicine, Tongji University, Shanghai, China. (3) Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Skin Cancer Center, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Institute of Photomedicine, School of Medicine, Tongji University, Shanghai, China. (4) Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Skin Cancer Center, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, China. Institute of Photomedicine, School of Medicine, Tongji University, Shanghai, China.

Citation: Front Immunol 2024 15:1369626 Epub04/16/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/38690273

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