Biselective remodeling of the melanoma tumor microenvironment prevents metastasis and enhances immune activation in mouse models
(1) Afratis NA (2) Parikh S (3) Adir I (4) Parikh R (5) Solomonov I (6) Kollet O (7) Gelb S (8) Sade Y (9) Vaknine H (10) Zemser-Werner V (11) Brener R (12) Nizri E (13) Hershkovitz D (14) Ricard-Blum S (15) Levy C (16) Sagi I
Dendritic cell progenitors engineered to express extracellular-vesicle-internalizing receptors enhance cancer immunotherapy in mouse models
(1) Ghasemi A (2) Martinez-Usatorre A (3) Liu Y (4) Demagny H (5) Li L (6) Mohammadzadeh Y (7) Hurtado A (8) Hicham M (9) Henneman L (10) Pritchard CEJ (11) Speiser DE (12) Migliorini D (13) De Palma M
(1) Ghasemi A (2) Martinez-Usatorre A (3) Liu Y (4) Demagny H (5) Li L (6) Mohammadzadeh Y (7) Hurtado A (8) Hicham M (9) Henneman L (10) Pritchard CEJ (11) Speiser DE (12) Migliorini D (13) De Palma M
Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer
Author Info: (1) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (2) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (3) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (4) Laboratory of Metabolic Signaling, Institute of Bioengineering, EPFL, Lausanne, Switzerland. (5) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (6) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (7) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (8) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. (9) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (10) Animal Modeling Facility, Netherlands Cancer Institute (NKI), Amsterdam, The Netherlands. (11) Department of Oncology, University of Lausanne (UNIL), Lausanne, Switzerland. Department of Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland. (12) Agora Cancer Research Center, Lausanne, Switzerland. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. Department of Oncology, Geneva University Hospital (HUG), Geneva, Switzerland. Center for Translational Research in Onco-Hematology, University of Geneva (UNIGE), Geneva, Switzerland. (13) Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology in Lausanne (EPFL), Lausanne, Switzerland. michele.depalma@epfl.ch. Agora Cancer Research Center, Lausanne, Switzerland. michele.depalma@epfl.ch. Swiss Cancer Center Lman (SCCL), Lausanne, Switzerland. michele.depalma@epfl.ch.
Citation: Nat Commun 2025 Oct 15 16:9148 Epub10/15/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41093860
Tags:
A next-generation anti-CTLA-4 probody mitigates toxicity and enhances anti-tumor immunity in mice
(1) Cao W (2) Chen J (3) Fu Y (4) Jiang H (5) Gao Y (6) Huang H (7) Fu YX (8) Wang W
(1) Cao W (2) Chen J (3) Fu Y (4) Jiang H (5) Gao Y (6) Huang H (7) Fu YX (8) Wang W
Author Info: (1) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijin
Author Info: (1) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (2) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (3) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (4) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (5) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (6) School of Basic Medical Sciences, Tsinghua University, Beijing, China. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. (7) School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. yangxinfu@tsinghua.edu.cn. Changping Laboratory, Changping District, Beijing, China. yangxinfu@tsinghua.edu.cn. (8) School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn. State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing, China. wywang2022@tsinghua.edu.cn.
Citation: Nat Commun 2025 Oct 10 16:9029 Epub10/10/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41073424
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IL-2/IL-15 signaling induces NK cell production of FLT3LG augmenting anti-PD-1 immunotherapy
(1) Avanessian SC (2) van den Bijgaart RJE (3) Chew NW (4) Supper VM (5) Tang TT (6) Zhang Y (7) Zhao YQ (8) Abe K (9) Gauthier J (10) Barry KC
(1) Avanessian SC (2) van den Bijgaart RJE (3) Chew NW (4) Supper VM (5) Tang TT (6) Zhang Y (7) Zhao YQ (8) Abe K (9) Gauthier J (10) Barry KC
Author Info: (1) Fred Hutchinson Cancer Center, United States. (2) Fred Hutchinson Cancer Center, United States. (3) Fred Hutchinson Cancer Center, Seattle, WA, United States. (4) Massachusetts
Author Info: (1) Fred Hutchinson Cancer Center, United States. (2) Fred Hutchinson Cancer Center, United States. (3) Fred Hutchinson Cancer Center, Seattle, WA, United States. (4) Massachusetts General Hospital Cancer Center, Boston, Massachusetts, United States. (5) Fred Hutchinson Cancer Center, Seattle, WA, United States. (6) Fred Hutchinson Cancer Center, Seattle, United States. (7) Fred Hutchinson Cancer Center, United States. (8) Fred Hutchinson Cancer Center, Seattle, WA, United States. (9) Fred Hutchinson Cancer Center, Seattle, France. (10) Fred Hutchinson Cancer Center, Seattle, WA, United States.
Citation: Cancer Immunol Res 2025 Oct 13 Epub10/13/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41081432
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Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia
(1) Sandn C (2) Landberg N (3) Pea-Martnez P (4) Thorsson H (5) Daga S (6) Puente-Moncada N (7) Rodriguez-Zabala M (8) von Palffy S (9) Rissler M (10) Lazarevic V (11) Juliusson G (12) Ohlin M (13) Hyrenius-Wittsten A (14) Orsmark-Pietras C (15) Lilljebjrn H (16) gerstam H (17) Fioretos T
(1) Sandn C (2) Landberg N (3) Pea-Martnez P (4) Thorsson H (5) Daga S (6) Puente-Moncada N (7) Rodriguez-Zabala M (8) von Palffy S (9) Rissler M (10) Lazarevic V (11) Juliusson G (12) Ohlin M (13) Hyrenius-Wittsten A (14) Orsmark-Pietras C (15) Lilljebjrn H (16) gerstam H (17) Fioretos T
Author Info: (1) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. carl.sanden@med.lu.se. (2) Division of Clinical Genetics, Department of Laborat
Author Info: (1) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. carl.sanden@med.lu.se. (2) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (3) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (4) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (5) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (6) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (7) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (8) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (9) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (10) Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (11) Department of Hematology, Oncology and Radiation Physics, Skne University Hospital, Lund, Sweden. (12) Department of Immunotechnology, Lund University, Lund, Sweden. SciLifeLab Drug Discovery and Development Platform, Lund University, Lund, Sweden. (13) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (14) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. (15) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. (16) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. (17) Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden. thoas.fioretos@med.lu.se. Department of Clinical Genetics, Pathology, and Molecular Diagnostics, Skne University Hospital, Region Skne, Lund, Sweden. thoas.fioretos@med.lu.se.
Citation: Nat Cancer 2025 Oct 3 Epub10/03/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41044242
Tags:
Local delivery of IL-15 and anti-PD-L1 nanobody by in vitro-transcribed circILNb elicits superior antitumor immunity in cold tumors
(1) Niu D (2) Ma X (3) Zhu J (4) Sun L (5) Zhang S (6) Wu Y (7) Shan M (8) Dai X (9) Liao Y (10) Liu D (11) Lu L (12) Yang M (13) Zou Q (14) Lian J
(1) Niu D (2) Ma X (3) Zhu J (4) Sun L (5) Zhang S (6) Wu Y (7) Shan M (8) Dai X (9) Liao Y (10) Liu D (11) Lu L (12) Yang M (13) Zou Q (14) Lian J
Author Info: (1) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (2) Department of Clinical Biochemistry, Fac
Author Info: (1) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (2) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (3) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (4) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (5) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (6) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (7) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (8) College of Education and Science, Chongqing Normal University, Chongqing 400047, China. (9) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (10) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (11) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. (12) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: yangmingzhen0807@126.com. (13) National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: qmzou2007@163.com. (14) Department of Clinical Biochemistry, Faculty of Pharmacy and Laboratory Medicine, Army Medical University, Chongqing 400038, China. Electronic address: lianjiqin@tmmu.edu.cn.
Citation: Cell Rep Med 2025 Oct 10 102413 Epub10/10/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41075789
Serial multiomics uncovers anti-glioblastoma responses not evident by routine clinical analyses
(1) Ling AL (2) Gantchev J (3) Prabhu MC (4) Basu S (5) Ahn R (6) D'Souza A (7) Masud N (8) Ball A (9) Nikas O (10) Villa GR (11) Regan MS (12) Baquer G (13) Ayoub G (14) Whittaker CA (15) Abou-Mrad Z (16) Santos A (17) Couturier CP (18) Elharouni D (19) Vogelzang J (20) Yu KKH (21) Chen H (22) He Z (23) Jiang W (24) Lucas CH (25) Sax HE (26) Lang FF (27) Puduvalli VK (28) Tabar V (29) W Brennan C (30) Boire A (31) Holdhoff M (32) Bettegowda C (33) Cima M (34) Solomon IH (35) Yuan Y (36) Tak PP (37) Sharma P (38) White FM (39) Ligon KL (40) Agar NYR (41) Reardon DA (42) Oliveira G (43) Chiocca EA
Ling et al. provided a longitudinal multiomic view of human glioblastoma (GBM) evolution under intratumoral oncolytic viral therapy (CAN-3110), demonstrating the feasibility and importance of serial tumor sampling in studying therapeutic response. Spatial and temporal remodeling of the tumor microenvironment was mapped across 86 serial GBM biopsies from two patients. Multiomic analysis revealed therapeutic response, longitudinal and spatial reshaping of the tumor, expansion of HSV-reactive and tumor-specific T cell clonotypes, and enhanced HLA and cancer testis antigen presentation, despite indications of disease progression by MRI.
Contributed by Shishir Pant
(1) Ling AL (2) Gantchev J (3) Prabhu MC (4) Basu S (5) Ahn R (6) D'Souza A (7) Masud N (8) Ball A (9) Nikas O (10) Villa GR (11) Regan MS (12) Baquer G (13) Ayoub G (14) Whittaker CA (15) Abou-Mrad Z (16) Santos A (17) Couturier CP (18) Elharouni D (19) Vogelzang J (20) Yu KKH (21) Chen H (22) He Z (23) Jiang W (24) Lucas CH (25) Sax HE (26) Lang FF (27) Puduvalli VK (28) Tabar V (29) W Brennan C (30) Boire A (31) Holdhoff M (32) Bettegowda C (33) Cima M (34) Solomon IH (35) Yuan Y (36) Tak PP (37) Sharma P (38) White FM (39) Ligon KL (40) Agar NYR (41) Reardon DA (42) Oliveira G (43) Chiocca EA
Ling et al. provided a longitudinal multiomic view of human glioblastoma (GBM) evolution under intratumoral oncolytic viral therapy (CAN-3110), demonstrating the feasibility and importance of serial tumor sampling in studying therapeutic response. Spatial and temporal remodeling of the tumor microenvironment was mapped across 86 serial GBM biopsies from two patients. Multiomic analysis revealed therapeutic response, longitudinal and spatial reshaping of the tumor, expansion of HSV-reactive and tumor-specific T cell clonotypes, and enhanced HLA and cancer testis antigen presentation, despite indications of disease progression by MRI.
Contributed by Shishir Pant
ABSTRACT: Recurrent glioblastoma (rGBM) remains incurable. One barrier to the development of effective rGBM therapies is the difficulty in collecting posttreatment tumor tissue. Serial multiomic assays from longitudinal rGBM biopsies may uncover tumor responses to a treatment. Here, we obtained 97 serial rGBM biopsy cores over 4 months from the first two patients participating in a clinical trial of repeated intratumoral dosing of the immunotherapeutic agent CAN-3110. Multiomic analysis of the biopsy cores revealed therapeutic effects, including longitudinal and spatial reshaping of the rGBM's microenvironment, expansion of new T cell tissue-resident effector memory clonotypes against CAN-3110 epitopes and other undetermined antigens, and expression of human leukocyte antigen (HLA)-presented immunopeptides, including cancer testis antigens. Moreover, serial integrated multimodal analyses provided evidence of therapeutic responses to CAN-3110 despite traditional magnetic resonance imaging indicating progression. Clinically, the two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand rGBM's evolution during administration of an investigational therapy.
Author Info: (1) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical Sc
Author Info: (1) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (2) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (3) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (4) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (5) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (6) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (7) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (8) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (9) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (10) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (11) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (12) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (13) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (14) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (15) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (17) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3AOG4, Canada. (18) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (19) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (20) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (21) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (22) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (23) Department of Radiation Oncology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (24) Department of Pathology, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (26) Department of Neurosurgery, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (27) Department of Neuro-Oncology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (28) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (29) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (30) Department of Neurology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (31) Division of Neuro-Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (32) Department of Neurosurgery, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (33) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (34) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (35) Department of Biostatistics, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (36) Candel Therapeutics Inc., Needham, MA 02494, USA. Accelerating GBM Therapies TeamLab, Cambridge, MA 02142, USA. (37) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. Department of Immunology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (38) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (39) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (40) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (41) Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (42) Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (43) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Citation: Sci Transl Med 2025 Oct 8 17:eadv2881 Epub10/08/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41061048
Recurrent immunogenic neoantigens and their cognate T-cell receptors in treatment-resistant metastatic prostate cancer
(1) Gumpert N (2) Sagie S (3) Arnedo-Pac C (4) Babu T (5) Weller C (6) Gonzalez-Perez A (7) Wang Y (8) Michel Tod L (9) Levy R (10) Chen X (11) Greenberg P (12) Dayan-Rubinov M (13) Yakubovich E (14) Wasserman-Bartov T (15) Zerbib M (16) Gong J (17) Rebernick RJ (18) Oliveira Tercero A (19) Agundez Muriel L (20) Benedek G (21) Kedmi M (22) Oren R (23) Ben-Dor S (24) Levin Y (25) Troyanskaya OG (26) Munzur AD (27) Wyatt AW (28) Cieslik MP (29) Quigley DA (30) Van Allen EM (31) Anandasabapathy N (32) Mateo J (33) Yang X (34) Martnez-Jimnez F (35) Lopez-Bigas N (36) Samuels Y
To systematically identify recurrent clonal neoepitopes in treatment-resistant patients, Gumbert and Sagie et al. developed and applied the “Spot Neoantigens in Metastases” (SpotNeoMet) pipeline to metastatic cancer samples from the Hartwig Medical Foundation, using primary tumor samples from TCGA as control. Focusing on the common androgen receptor (AR) H875Y mutation in castration-resistant prostate cancer, they identified three neopeptides and validated their presentation and immunogenicity. Two cloned cognate TCRs were highly specific and led to killing of prostate cancer cells endogenously expressing AR H875Y in vitro and in vivo.
Contributed by Ute Burkhardt
(1) Gumpert N (2) Sagie S (3) Arnedo-Pac C (4) Babu T (5) Weller C (6) Gonzalez-Perez A (7) Wang Y (8) Michel Tod L (9) Levy R (10) Chen X (11) Greenberg P (12) Dayan-Rubinov M (13) Yakubovich E (14) Wasserman-Bartov T (15) Zerbib M (16) Gong J (17) Rebernick RJ (18) Oliveira Tercero A (19) Agundez Muriel L (20) Benedek G (21) Kedmi M (22) Oren R (23) Ben-Dor S (24) Levin Y (25) Troyanskaya OG (26) Munzur AD (27) Wyatt AW (28) Cieslik MP (29) Quigley DA (30) Van Allen EM (31) Anandasabapathy N (32) Mateo J (33) Yang X (34) Martnez-Jimnez F (35) Lopez-Bigas N (36) Samuels Y
To systematically identify recurrent clonal neoepitopes in treatment-resistant patients, Gumbert and Sagie et al. developed and applied the “Spot Neoantigens in Metastases” (SpotNeoMet) pipeline to metastatic cancer samples from the Hartwig Medical Foundation, using primary tumor samples from TCGA as control. Focusing on the common androgen receptor (AR) H875Y mutation in castration-resistant prostate cancer, they identified three neopeptides and validated their presentation and immunogenicity. Two cloned cognate TCRs were highly specific and led to killing of prostate cancer cells endogenously expressing AR H875Y in vitro and in vivo.
Contributed by Ute Burkhardt
ABSTRACT: New approaches that generate long-lasting therapeutic responses in therapy-resistant metastatic cancer patients are urgently needed. To address this challenge, we developed SpotNeoMet, a novel data-driven pipeline that systematically identifies recurrently presented neopeptides in treatment-resistant patients. We identified seven therapy resistance mutations predicted to produce neo-peptides presented by common HLAs. Using HLA-immunopeptidomics, we discovered three novel neopeptides derived from Androgen Receptor (AR) H875Y, a common metastatic castration-resistant prostate cancer (mCRPC) mutation. We validated these neoantigens as highly immunogenic and then isolated and characterized cognate T-cell receptors (TCRs) from healthy donor peripheral blood mononuclear cells. We demonstrated that AR H875Y specific TCRs are highly specific and kill prostate cancer cells presenting AR neo-peptides in vitro and in vivo. Our new pipeline identifies novel immunotherapy targets and potential treatment options for mCRPC patients. Moreover, SpotNeoMet offers a systematic route to identify 'HLA-peptide' pairs and their cognate TCRs across treatment-resistant cancers.
Author Info: (1) Weizmann Institute of Science, Rehovot, Israel. (2) Weizmann Institute of Science, Rehovot, Israel. (3) Institute for Research in Biomedicine, Barcelona, Spain. (4) Weizmann In
Author Info: (1) Weizmann Institute of Science, Rehovot, Israel. (2) Weizmann Institute of Science, Rehovot, Israel. (3) Institute for Research in Biomedicine, Barcelona, Spain. (4) Weizmann Institute of Science, Rehovot, Israel. (5) Weizmann Institute of Science, Rehovot, Israel. (6) Institute for Research in Biomedicine, Barcelona, Spain. (7) Princeton University, Princeton, NJ, United States. (8) Vall d'Hebron Institute of Oncology, Spain. (9) Weizmann Institute of Science, Rehovot, Israel. (10) Flatiron Institute, New York, NY, United States. (11) Weizmann Institute of Science, Rehovot, Israel. (12) Weizmann Institute of Science, Israel. (13) Weizmann Institute of Science, Rehovot, Israel. (14) Weizmann Institute of Science, Israel. (15) Weizmann Institute of Science, Rehovot, Israel, Israel. (16) University of Michigan-Ann Arbor, Ann Arbor, United States. (17) University of Michigan-Ann Arbor, Ann Arbor, United States. (18) Vall d'Hebron Institute of Oncology, Barcelona, Barcelona, Spain. (19) Vall d'Hebron Institute of Oncology, Spain. (20) Hadassah Medical Center, Jerusalem, Israel. (21) Weizmann Institute of Science, Israel. (22) Weizmann institute, Rehovot, Israel, Israel. (23) Weizmann Institute of Science, Rehovot, Israel, Israel. (24) Weizmann Institute of Science, Rehovot, Israel. (25) Princeton University, Princeton, NJ, United States. (26) University of British Columbia, Vancouver, British Columbia, Canada. (27) University of British Columbia, Vancouver, British Columbia, Canada. (28) University of Michigan-Ann Arbor, Ann Arbor, MI, United States. (29) University of California, San Francisco, San Francisco, CA, United States. (30) Dana-Farber Cancer Institute, Boston, MA, United States. (31) Weill Cornell Medicine, New York, NY, United States. (32) Vall d'Hebron Institute of Oncology, Barcelona, Spain. (33) Memorial Sloan Kettering Cancer Center, United States. (34) Vall d'Hebron Institute of Oncology, Spain. (35) Institute for Research in Biomedicine, Barcelona, Spain. (36) Weizmann Institute of Science, Rehovot, Israel.
Citation: Cancer Discov 2025 Oct 8 Epub10/08/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41056506
Replacing cholesterol and PEGylated lipids with zwitterionic ionizable lipids in LNPs for spleen-specific mRNA translation
(1) Zhao Y (2) Tian Z (3) Wang J (4) Cui M (5) Cao Z (6) Liu P (7) Li R (8) Cai S (9) Hu Y (10) Ma Y (11) Wagner E (12) Laflin A (13) Gu W (14) Cui Y (15) Tang C (16) Fountain H (17) Wang R (18) Jiang S
Zhao, Tian, Wang, et al. developed a new mRNA therapeutic cancer vaccine formulation that replaces cholesterol and PEGylated lipids in lipid nanoparticles (LNPs) with zwitterionic pyridine carboxybetaine ionizable lipids. This change increased spleen mRNA translation, reduced liver accumulation, and prevented immunogenicity against the vaccine upon repeat administration. The vaccine formulation induced specific CD8+ T cell responses, Tem and Tcm responses, and improved tumor control in murine models.
(1) Zhao Y (2) Tian Z (3) Wang J (4) Cui M (5) Cao Z (6) Liu P (7) Li R (8) Cai S (9) Hu Y (10) Ma Y (11) Wagner E (12) Laflin A (13) Gu W (14) Cui Y (15) Tang C (16) Fountain H (17) Wang R (18) Jiang S
Zhao, Tian, Wang, et al. developed a new mRNA therapeutic cancer vaccine formulation that replaces cholesterol and PEGylated lipids in lipid nanoparticles (LNPs) with zwitterionic pyridine carboxybetaine ionizable lipids. This change increased spleen mRNA translation, reduced liver accumulation, and prevented immunogenicity against the vaccine upon repeat administration. The vaccine formulation induced specific CD8+ T cell responses, Tem and Tcm responses, and improved tumor control in murine models.
ABSTRACT: The spleen is emerging as a key vaccination target. However, existing lipid nanoparticles (LNPs) primarily accumulate in the liver, limiting their efficacy in vaccine therapy. The cholesterol in current LNP formulations promotes their uptake by hepatocytes, while the polyethylene glycol-modified (PEGylated) lipids induce PEG immunogenicity, further reducing the efficacy in the setting of repeated administrations. We develop a three-component (ThrCo) LNP by replacing cholesterol and PEGylated lipids in Pfizer-BioNTech LNPs with zwitterionic pyridine carboxybetaine (PyCB) ionizable lipids (ILs), achieving ~70% lower liver accumulation and a 4.5-fold increase in spleen-specific mRNA translation. PyCB ILs enhance LNP hydrophilicity, stabilizing the outer membrane to compensate for cholesterol removal. PyCB groups also exhibit strong protonation at endosomal pH, facilitating mRNA translation. The zwitterionic surface of ThrCo LNP reduces protein adsorption, thereby preventing the accelerated blood clearance effect caused by PEGylated lipids following repeated administrations. Thus, ThrCo LNP-based vaccines efficiently deliver mRNA to splenic antigen-presenting cells, boosting immune responses and improving therapeutic outcomes.
Author Info: (1) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (2) Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 1
Author Info: (1) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (2) Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA. (3) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (4) Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA. (5) Department of Materials Science and Engineering, Cornell University, Ithaca, NY 14853, USA. (6) Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA. (7) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (8) Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA. (9) Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA. (10) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (11) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (12) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (13) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (14) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (15) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (16) Department of Biological and Biomedical Sciences, Cornell University, Ithaca, NY 14853, USA. (17) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. (18) Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
Citation: Sci Adv 2025 Oct 10 11:eady6460 Epub10/08/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41061074
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Combination LIGHT overexpression and checkpoint blockade disrupts the tumor immune environment impacting colorectal liver metastases
(1) Keenan BP (2) Qiao G (3) Kunda N (4) Kone L (5) Guldberg SM (6) Todeschini L (7) Kumar P (8) Pollini T (9) Hernandez S (10) Qin J (11) Fong L (12) Spitzer MH (13) Prabhakar BS (14) Maker AV
Keenan and Qiao et al. showed in mouse models of colorectal liver metastases (CRLMs, which are CTLA-4high) that anti-CTLA-4 (but not anti-PD-1) treatment controlled LIGHT-overexpressing CRLMs by generating systemic and intratumoral immune activation. scRNAseq, CyTOF, and flow cytometry showed that the LIGHT/anti-CTLA-4 combination remodeled the TME; promoted TIL migration into metastases, TLS development, activation and effector functions of T cells and DC maturation; decreased T cell exhaustion; depleted suppressive myeloid cells; and reduced Treg functionality, with some corresponding data in human CRC.
Contributed by Paula Hochman
(1) Keenan BP (2) Qiao G (3) Kunda N (4) Kone L (5) Guldberg SM (6) Todeschini L (7) Kumar P (8) Pollini T (9) Hernandez S (10) Qin J (11) Fong L (12) Spitzer MH (13) Prabhakar BS (14) Maker AV
Keenan and Qiao et al. showed in mouse models of colorectal liver metastases (CRLMs, which are CTLA-4high) that anti-CTLA-4 (but not anti-PD-1) treatment controlled LIGHT-overexpressing CRLMs by generating systemic and intratumoral immune activation. scRNAseq, CyTOF, and flow cytometry showed that the LIGHT/anti-CTLA-4 combination remodeled the TME; promoted TIL migration into metastases, TLS development, activation and effector functions of T cells and DC maturation; decreased T cell exhaustion; depleted suppressive myeloid cells; and reduced Treg functionality, with some corresponding data in human CRC.
Contributed by Paula Hochman
ABSTRACT: Colorectal cancer and liver metastases are a leading cause of cancer-related mortality. Overexpression of the immunostimulatory cytokine TNFSF14/LIGHT associates with improved survival and correlates with increased tumor-infiltrating lymphocytes in patients and a clinically relevant model of colorectal liver metastases. We demonstrate that LIGHT monotherapy activates T cells, but also induces T cell exhaustion and the recruitment of immunosuppressive elements. As colorectal liver metastases exhibit high levels of CTLA-4 expression, we combined LIGHT overexpression with anti-CTLA-4, leading to complete tumor control. The combination functions by homing tumor-infiltrating lymphocytes, inducing tumor antigen-specific T cells, and reversing T cell exhaustion. Whereas both LIGHT overexpression and anti-CTLA-4 increase tumor-promoting macrophages, the combination eliminates this population. The ability of LIGHT overexpression combined with CTLA-4 inhibition to reverse T cell exhaustion and myeloid cell suppression is supported by analysis of complementary patient cohorts and has strong clinical relevance, especially given that liver metastases contribute to immunotherapy resistance across various cancer types.
Author Info: (1) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Surgery, Division of Surgical
Author Info: (1) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (3) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (4) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (5) Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. (6) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (8) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (9) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. (10) Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (11) Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. (12) Departments of Otolaryngology-Head and Neck Surgery and Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. Chan Zuckerberg Biohub, San Francisco, CA 94158, USA. (13) Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612, USA. (14) Department of Surgery, Division of Surgical Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
Citation: Sci Adv 2025 Oct 10 11:eadv9161 Epub10/08/2025
Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/41061056