Journal Articles

Succinate-loaded tumor cell-derived microparticles reprogram tumor-associated macrophage metabolism Spotlight 

(1) Lu S (2) Li J (3) Li Y (4) Liu S (5) Liu Y (6) Liang Y (7) Zheng X (8) Chen Y (9) Deng J (10) Zhang H (11) Ma J (12) Lv J (13) Wang Y (14) Huang B (15) Tang K

Science translational medicine

To reprogram M2-like macrophages in the TME and enhance their antitumor efficacy, Lu and Li et al. used electroporation to load tumor cell membrane-derived microparticles with succinate (SMPs), which delivered succinate intracellularly into mitochondria and the nucleus of macrophages. SMPs, but not free succinate, induced succinylation of isocitrate dehydrogenase 2 (promoting HIF-1α stabilization) and histone H3K122 (promoting lactate dehydrogenase A expression), resulting in increased glycolysis, TCA cycle attenuation, and metabolic reprogramming of TAMs into M1 polarized macrophages. SMPs inhibited tumor progression and increased survival in several murine tumor models.

Contributed by Katherine Turner

(1) Lu S (2) Li J (3) Li Y (4) Liu S (5) Liu Y (6) Liang Y (7) Zheng X (8) Chen Y (9) Deng J (10) Zhang H (11) Ma J (12) Lv J (13) Wang Y (14) Huang B (15) Tang K

Science translational medicine

To reprogram M2-like macrophages in the TME and enhance their antitumor efficacy, Lu and Li et al. used electroporation to load tumor cell membrane-derived microparticles with succinate (SMPs), which delivered succinate intracellularly into mitochondria and the nucleus of macrophages. SMPs, but not free succinate, induced succinylation of isocitrate dehydrogenase 2 (promoting HIF-1α stabilization) and histone H3K122 (promoting lactate dehydrogenase A expression), resulting in increased glycolysis, TCA cycle attenuation, and metabolic reprogramming of TAMs into M1 polarized macrophages. SMPs inhibited tumor progression and increased survival in several murine tumor models.

Contributed by Katherine Turner

ABSTRACT: The tumor microenvironment predominantly polarizes tumor-associated macrophages (TAMs) toward an M2-like phenotype, thereby inhibiting antitumor immune responses. This process is substantially affected by metabolic reprogramming; however, reeducating TAMs to enhance their antitumor capabilities through metabolic remodeling remains a challenge. Here, we show that tumor-derived microparticles loaded with succinate (SMPs) can remodel the metabolic state of TAMs. SMPs promote classical M1-like polarization of macrophages by enhancing glycolysis and attenuating the tricarboxylic acid (TCA) cycle in a protein succinylation-dependent manner. Mechanistically, succinate is delivered into the mitochondria and nucleus by SMPs, leading to succinylation of isocitrate dehydrogenase 2 (IDH2) and histone H3K122 within the lactate dehydrogenase A (Ldha) promoter region. Our findings provide a distinct approach for TAM polarization using cell membrane-derived microparticles loaded with endogenous metabolites, a platform that may be used more broadly for posttranslational modification-based tumor immunotherapy.

Author Info: (1) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (2) Department of Biochemistry and

Author Info: (1) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (2) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China. (3) Hubei Provincial Key Laboratory for Applied Toxicology, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, China. (4) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (5) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (6) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (7) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (8) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (9) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (10) Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (11) Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. (12) Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China. (13) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan 430030, China. (14) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Department of Immunology & State Key Laboratory of Common Mechanism Research for Major Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China. (15) Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China. Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan 430030, China.

Citation: Sci Transl Med 2025 Apr 9 17:eadr4458 Epub04/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40203081

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Neoantigen-specific tumor-infiltrating lymphocytes in gastrointestinal cancers: a phase 2 trial Spotlight 

(1) Lowery FJ (2) Goff SL (3) Gasmi B (4) Parkhurst MR (5) Ratnam NM (6) Halas HK (7) Shelton TE (8) Langhan MM (9) Bhasin A (10) Dinerman AJ (11) Dulemba V (12) Goldlust IS (13) Gustafson AM (14) Hakim AA (15) Hitscherich KJ (16) Kenney LM (17) Levy L (18) Rault-Wang JG (19) Bera A (20) Ray S (21) Seavey CD (22) Hoang CD (23) Hernandez JM (24) Gartner JJ (25) Sindiri S (26) Prickett TD (27) McIntyre LS (28) Krishna S (29) Robbins PF (30) Klemen ND (31) Kwong MLM (32) Yang JC (33) Rosenberg SA

Nature medicine

Patients with heavily pretreated metastatic GI cancers were treated with neoantigen-reactive TILs alone (SEL-TIL) or with pembrolizumab (SEL-TIL+P). 15.1% of SEL-TIL and 23.5% of SEL-TIL+P patients had a PR, and 8 additional patients experienced target lesion reduction of >30%. Serious AEs occurred in 30% of patients, with 7 requiring critical care and one infection-related death. Responders’ TIL products were reactive to a significantly greater number of neoantigens and contained a greater number of reactive CD4+, but not CD8+ T cells, while their tumors were enriched for pathways related to inflammation and wound healing.

Contributed by Morgan Janes

(1) Lowery FJ (2) Goff SL (3) Gasmi B (4) Parkhurst MR (5) Ratnam NM (6) Halas HK (7) Shelton TE (8) Langhan MM (9) Bhasin A (10) Dinerman AJ (11) Dulemba V (12) Goldlust IS (13) Gustafson AM (14) Hakim AA (15) Hitscherich KJ (16) Kenney LM (17) Levy L (18) Rault-Wang JG (19) Bera A (20) Ray S (21) Seavey CD (22) Hoang CD (23) Hernandez JM (24) Gartner JJ (25) Sindiri S (26) Prickett TD (27) McIntyre LS (28) Krishna S (29) Robbins PF (30) Klemen ND (31) Kwong MLM (32) Yang JC (33) Rosenberg SA

Nature medicine

Patients with heavily pretreated metastatic GI cancers were treated with neoantigen-reactive TILs alone (SEL-TIL) or with pembrolizumab (SEL-TIL+P). 15.1% of SEL-TIL and 23.5% of SEL-TIL+P patients had a PR, and 8 additional patients experienced target lesion reduction of >30%. Serious AEs occurred in 30% of patients, with 7 requiring critical care and one infection-related death. Responders’ TIL products were reactive to a significantly greater number of neoantigens and contained a greater number of reactive CD4+, but not CD8+ T cells, while their tumors were enriched for pathways related to inflammation and wound healing.

Contributed by Morgan Janes

ABSTRACT: Adoptive transfer of unselected autologous tumor-infiltrating lymphocytes (TILs) has mediated meaningful clinical responses in patients with metastatic melanoma but not in cancers of gastrointestinal epithelial origin. In an evolving single-arm phase 2 trial design, TILs were derived from and administered to 91 patients with treatment-refractory mismatch repair proficient metastatic gastrointestinal cancers in a schema with lymphodepleting chemotherapy and high-dose interleukin-2 (three cohorts of an ongoing trial). The primary endpoint of this study was the objective response rate as measured using Response Evaluation Criteria in Solid Tumors 1.0; safety was a descriptive secondary endpoint. In the pilot phase, no clinical responses were observed in 18 patients to bulk, unselected TILs; however, when TILs were screened and selected for neoantigen recognition (SEL-TIL), three responses were seen in 39 patients (7.7% (95% confidence interval (CI): 2.7-20.3)). Based on the high levels of programmed cell death protein 1 in the infused TILs, pembrolizumab was added to the regimen (SEL-TIL + P), and eight objective responses were seen in 34 patients (23.5% (95% CI: 12.4-40.0)). All patients experienced transient severe hematologic toxicities from chemotherapy. Seven (10%) patients required critical care support. Exploratory analyses for laboratory and clinical correlates of response were performed for the SEL-TIL and SEL-TIL + P treatment arms. Response was associated with recognition of an increased number of targeted neoantigens and an increased number of administered CD4(+) neoantigen-reactive TILs. The current strategy (SEL-TIL + P) exceeded the parameters of the trial design for patients with colorectal cancer, and an expansion phase is accruing. These results could potentially provide a cell-based treatment in a population not traditionally expected to respond to immunotherapy. ClinicalTrials.gov identifier: NCT01174121 .

Author Info: (1) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (2) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, M

Author Info: (1) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (2) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. stephanie.goff@nih.gov. (3) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (4) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (5) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (6) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (7) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (8) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (9) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (10) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (11) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (12) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (13) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (14) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (15) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (16) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (17) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (18) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (19) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (20) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (21) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (22) National Cancer Institute, Center for Cancer Research, Thoracic Surgery Branch, Bethesda, MD, USA. (23) National Cancer Institute, Center for Cancer Research, Surgical Oncology Program, Bethesda, MD, USA. (24) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (25) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (26) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (27) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (28) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (29) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (30) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (31) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (32) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. (33) National Cancer Institute, Center for Cancer Research, Surgery Branch, Bethesda, MD, USA. sar@nih.gov.

Citation: Nat Med 2025 Apr 1 Epub04/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40169866

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Allogeneic NK cells with a bispecific innate cell engager in refractory relapsed lymphoma: a phase 1 trial

Spotlight 

(1) Nieto Y (2) Banerjee P (3) Kaur I (4) Basar R (5) Li Y (6) Daher M (7) Rafei H (8) Kerbauy LN (9) Kaplan M (10) Marin D (11) Griffin L (12) Barnett M (13) Bassett R (14) Uprety N (15) Shrestha R (16) Silva FR (17) Islam S (18) Ganesh C (19) Borneo Z (20) Ramdial J (21) Ramirez A (22) Hosing C (23) Alousi A (24) Popat U (25) Qazilbash M (26) Ahmed S (27) Iyer S (28) Sainz TP (29) Vega F (30) Fowlkes NW (31) Alexis K (32) Emig M (33) Harstrick A (34) Overesch A (35) Shpall EJ (36) Rezvani K

Nature medicine

Nieto et al. reported favorable safety profiles and preliminary activity of cord blood-derived cytokine-pre-activated and expanded NK cells pre-complexed with AFM13 – a CD30/CD16A bispecific antibody – in 42 patients with CD30+ lymphoma refractory to both brentuximab vedotin and anti-PD-1. AFM13-NK cell infusion with subsequent infusions of AFM13 were well tolerated, without CRS, neurotoxicity, or GvHD. Donor NK cells persisted up to 3 weeks, acquired an activated and cytotoxic phenotype, and trafficked to tumor sites. At a median follow-up of 20 months, EFS and OS were 26.2% and 76.2%, respectively. Eleven patients remained in CR at 12–40 months.

Contributed by Shishir Pant

(1) Nieto Y (2) Banerjee P (3) Kaur I (4) Basar R (5) Li Y (6) Daher M (7) Rafei H (8) Kerbauy LN (9) Kaplan M (10) Marin D (11) Griffin L (12) Barnett M (13) Bassett R (14) Uprety N (15) Shrestha R (16) Silva FR (17) Islam S (18) Ganesh C (19) Borneo Z (20) Ramdial J (21) Ramirez A (22) Hosing C (23) Alousi A (24) Popat U (25) Qazilbash M (26) Ahmed S (27) Iyer S (28) Sainz TP (29) Vega F (30) Fowlkes NW (31) Alexis K (32) Emig M (33) Harstrick A (34) Overesch A (35) Shpall EJ (36) Rezvani K

Nature medicine

Nieto et al. reported favorable safety profiles and preliminary activity of cord blood-derived cytokine-pre-activated and expanded NK cells pre-complexed with AFM13 – a CD30/CD16A bispecific antibody – in 42 patients with CD30+ lymphoma refractory to both brentuximab vedotin and anti-PD-1. AFM13-NK cell infusion with subsequent infusions of AFM13 were well tolerated, without CRS, neurotoxicity, or GvHD. Donor NK cells persisted up to 3 weeks, acquired an activated and cytotoxic phenotype, and trafficked to tumor sites. At a median follow-up of 20 months, EFS and OS were 26.2% and 76.2%, respectively. Eleven patients remained in CR at 12–40 months.

Contributed by Shishir Pant

ABSTRACT: Outcomes of patients with CD30-positive (CD30(+)) lymphomas have improved with the advent of brentuximab vedotin (BV) and, in Hodgkin lymphoma, anti-PD1 checkpoint inhibitors (CPI). However, there is a need for new therapies for patients with tumors refractory to both BV and CPI, who face dismal outcomes. AFM13-a CD30/CD16A bispecific antibody-activates natural killer (NK) cells to kill CD30(+) cells. Here we studied cord-blood-derived cytokine-preactivated and expanded NK cells precomplexed with AFM13 (AFM13-NK) in patients with CD30(+) lymphoma refractory to BV and CPI. The primary endpoint of this phase_1 trial was to establish the safety and recommended phase 2 dose of AFM13-NK followed by intravenous AFM13 infusions. Secondary endpoints included the overall response rate and complete response (CR) rate, event-free survival and overall survival, and persistence of infused AFM13-NK cells. This is the final analysis of this trial; 42 heavily pretreated patients received 2 to 4 cycles of lymphodepletion followed by AFM13-NK cell infusion at 3 dose levels (10(6), 10(7) and 10(8)_kg(-1)) and 3 weekly AFM13 infusions. No cytokine release syndrome, neurotoxicity or graft-versus-host disease was observed. The highest NK dose was established as the recommended phase_2 dose. Donor NK cells peaked in blood 1_day postinfusion, persisted up to 3_weeks and trafficked to tumor sites. The overall response and CR rates were 92.9% and 66.7%, respectively. At a median follow-up of 20_months, the 2-year event-free and overall survival rates were 26.2% and 76.2%, respectively. Eleven patients (6 with and 5 without consolidation) remained in CR at 14-40 months. This therapy showed encouraging preliminary safety and efficacy. ClinicalTrials.gov Identifier: NCT04074746 .

Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ynieto@mdanderson.org. (2) Department of Stem

Author Info: (1) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ynieto@mdanderson.org. (2) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (4) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (6) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (10) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (12) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (13) Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (15) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (19) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (20) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (24) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (25) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (26) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (28) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (29) Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (30) Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Affimed GmbH, Heidelberg, Germany. (32) Affimed GmbH, Heidelberg, Germany. (33) Affimed GmbH, Heidelberg, Germany. (34) Affimed GmbH, Heidelberg, Germany. (35) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (36) Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Institute for Cell Therapy Discovery and Innovation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Citation: Nat Med 2025 Apr 4 Epub04/04/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40186077

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A distinct priming phase regulates CD8 T cell immunity by orchestrating paracrine IL-2 signals Featured  

(1) Jobin K (2) Seetharama D (3) Rüttger L (4) Fenton C (5) Kharybina E (6) Wirsching A (7) Huang A (8) Knöpper K (9) Kaisho T (10) Busch DH (11) Vaeth M (12) Saliba AE (13) Graw F (14) Pulfer A (15) González SF (16) Zehn D (17) Liang Y (18) Ugur M (19) Gasteiger G (20) Kastenmüller W

Science

Jobin, Seetharama, et al. uncovered a second priming phase in draining lymph nodes, in which hours-long interactions between DCs and CD8+ T cells take place. This phase was found to be essential for clonal expansion and effector differentiation, specifically for high-affinity clones. The process was found to be dependent on CXCR3 expression on CD8+ T cells and the production of IL-2 by CD4+ T helper cells. Tregs regulated CD8+ T cell effector differentiation during this priming phase.

(1) Jobin K (2) Seetharama D (3) Rüttger L (4) Fenton C (5) Kharybina E (6) Wirsching A (7) Huang A (8) Knöpper K (9) Kaisho T (10) Busch DH (11) Vaeth M (12) Saliba AE (13) Graw F (14) Pulfer A (15) González SF (16) Zehn D (17) Liang Y (18) Ugur M (19) Gasteiger G (20) Kastenmüller W

Science

Jobin, Seetharama, et al. uncovered a second priming phase in draining lymph nodes, in which hours-long interactions between DCs and CD8+ T cells take place. This phase was found to be essential for clonal expansion and effector differentiation, specifically for high-affinity clones. The process was found to be dependent on CXCR3 expression on CD8+ T cells and the production of IL-2 by CD4+ T helper cells. Tregs regulated CD8+ T cell effector differentiation during this priming phase.

ABSTRACT: T cell priming is characterized by an initial activation phase that involves stable interactions with dendritic cells (DCs). How activated T cells receive the paracrine signals required for their differentiation once they have disengaged from DCs and resumed their migration has been unclear. We identified a distinct priming phase that favors CD8 T cells expressing receptors with high affinity for antigen. CXCR3 expression by CD8 T cells was required for their hours-long reengagement with DCs in specific subfollicular niches in lymph nodes. CD4 T cells paused briefly at the sites of CD8 T cell and DC interactions and provided Interleukin-2 (IL-2) before moving to another DC. Our results highlight a previously unappreciated phase of cell-cell interactions during T cell priming and have direct implications for vaccinations and cellular immunotherapies.

Author Info: (1) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (2) Würzburg Institute of Systems Immunolo

Author Info: (1) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (2) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (3) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (4) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (5) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (6) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (7) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (8) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburgg, Würzburg, Germany. (9) Department of Immunology, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan. (10) Institute for Medical Microbiology, Immunology and Hygiene, Technische Universitt München (TUM), Munich, Germany. (11) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (12) Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany. Institute of Molecular Infection Biology Faculty of Medicine, University of Würzburg, Würzburg, Germany. (13) Department of Internal Medicine 5 - Hematology and Oncology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany. (14) Istituto di Ricerca in Biomedicina (IRB), Università della Svizzera Italiana, Bellinzona, Switzerland. (15) Istituto di Ricerca in Biomedicina (IRB), Università della Svizzera Italiana, Bellinzona, Switzerland. (16) Division of Animal Physiology and Immunology, School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany. (17) The Laboratory of Genetic Regulators in the Immune System, School of Medical Technology, Xinxiang Medical University, Xinxiang, China. (18) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (19) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany. (20) Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-University Würzburg, Würzburg, Germany.

Citation: Science 2025 Apr 11 388:eadq1405 Epub04/11/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40208984

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Adoptively transferred tumor-specific IL-9-producing cytotoxic CD8+ T cells activate host CD4+ T cells to control tumors with antigen loss

Spotlight 

(1) Xiao L (2) Duan R (3) Liu W (4) Zhang C (5) Ma X (6) Xian M (7) Wang Q (8) Guo Q (9) Xiong W (10) Su P (11) Ye L (12) Li Y (13) Zhong L (14) Qian J (15) Lu Y (16) Zhao Z (17) Yi Q

Nature cancer

Xiao et al. demonstrated that adoptively transferred Tc9 cells (IL-9-producing cytotoxic CD8+ T cells) were able to control the growth of B16-OVA tumors, even upon antigen loss. Investigating the mechanism, they found that Tc9 cell secretion of IL-24 recruited CCR7+ cDC2s to tumors. These cDC2s migrated to tdLNs, where they primed host cytotoxic effector CD4+ T cells, which then infiltrated tumors and contributed to tumor growth control. In patient data for melanoma and breast cancer, intratumoral IL24 expression correlated with cDC2 and CD4+ T cell signatures, which were both associated with longer survival.

Contributed by Lauren Hitchings

(1) Xiao L (2) Duan R (3) Liu W (4) Zhang C (5) Ma X (6) Xian M (7) Wang Q (8) Guo Q (9) Xiong W (10) Su P (11) Ye L (12) Li Y (13) Zhong L (14) Qian J (15) Lu Y (16) Zhao Z (17) Yi Q

Nature cancer

Xiao et al. demonstrated that adoptively transferred Tc9 cells (IL-9-producing cytotoxic CD8+ T cells) were able to control the growth of B16-OVA tumors, even upon antigen loss. Investigating the mechanism, they found that Tc9 cell secretion of IL-24 recruited CCR7+ cDC2s to tumors. These cDC2s migrated to tdLNs, where they primed host cytotoxic effector CD4+ T cells, which then infiltrated tumors and contributed to tumor growth control. In patient data for melanoma and breast cancer, intratumoral IL24 expression correlated with cDC2 and CD4+ T cell signatures, which were both associated with longer survival.

Contributed by Lauren Hitchings

ABSTRACT: Host effector CD4(+) T cells emerge as critical mediators for tumor regression but whether they can be activated by adoptively transferred CD8(+) T cells remains unknown. We previously reported that adoptive transfer of interleukin 9 (IL-9)-producing cytotoxic CD8(+) T (Tc9) cells achieved long-term control of tumor growth. Here, we demonstrate that murine tumor-specific Tc9 cells control the outgrowth of antigen-loss relapsed tumors by recruiting and activating host effector CD4(+) T cells. Tc9 cells secreted IL-24 and recruited CCR7-expressing conventional type 2 dendritic cells (cDC2 cells) into tumor-draining lymph nodes to prime host CD4(+) T cells against relapsed tumors. Host CD4(+) T cell or cDC2 deficiency impaired the ability of Tc9 cells to control relapsed tumor outgrowth. Additionally, intratumoral IL24 expression correlates with cDC2 and CD4(+) T cell gene signatures in human cancers and their expression is associated with better patient survival. This study reports a mechanism for activation of tumor-specific CD4(+) T cells in vivo.

Author Info: (1) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. xiaoliuling@cqmu.edu.cn. First Affiliated Hospital, School of Basic Medicine, Chon

Author Info: (1) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. xiaoliuling@cqmu.edu.cn. First Affiliated Hospital, School of Basic Medicine, Chongqing Medical University, Chongqing, China. xiaoliuling@cqmu.edu.cn. (2) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (3) The University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA. (4) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (5) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (6) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (7) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (8) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (9) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (10) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (11) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (12) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (13) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (14) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (15) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. (16) The University of Texas MD Anderson Cancer Center, UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA. Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA. Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA. (17) Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, USA. qyi@houstonmethodist.org.

Citation: Nat Cancer 2025 Apr 3 Epub04/03/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40181089

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Autologous T cell therapy for PRAME+ advanced solid tumors in HLA-A*02+ patients: a phase 1 trial

Spotlight 

(1) Wermke M (2) Araurjo DM (3) Chatterjee M (4) Tsimberidou AM (5) Holderried TAW (6) Jazaeri AA (7) Reshef R (8) Bokemeyer C (9) Alsdorf W (10) Wetzko K (11) Brossart P (12) Aslan K (13) Backert L (14) Bunk S (15) Fritsche J (16) Gulde S (17) Hengler S (18) Hilf N (19) Hossain MB (20) Hukelmann J (21) Kalra M (22) Krishna D (23) Kursunel MA (24) Maurer D (25) Mayer-Mokler A (26) Mendrzyk R (27) Mohamed A (28) Pozo K (29) Satelli A (30) Letizia M (31) Schuster H (32) Schoor O (33) Wagner C (34) Rammensee HG (35) Reinhardt C (36) Singh-Jasuja H (37) Walter S (38) Weinschenk T (39) Luke JJ (40) Britten CM

Nature medicine

Wermke et al. reported interim data from a phase 1 dose-escalation trial of IMA203 – PRAME-directed autologous TCR T cell therapy – in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors. Although the PRAME TCR was pairing-optimized and affinity-enhanced, IMA203 was safe and well tolerated, without any treatment-related fatalities. IMA203 rapidly engrafted tumors and demonstrated long-term persistence. In the 40 patients treated with IMA203, the unconfirmed/confirmed (u/c)ORR was 52.5%, and the cORR was 28.9%, with a median duration of response of 4.4 months. Higher PRAME expression and T cell infiltration correlated with deeper responses and longer PFS.

Contributed by Shishir Pant

(1) Wermke M (2) Araurjo DM (3) Chatterjee M (4) Tsimberidou AM (5) Holderried TAW (6) Jazaeri AA (7) Reshef R (8) Bokemeyer C (9) Alsdorf W (10) Wetzko K (11) Brossart P (12) Aslan K (13) Backert L (14) Bunk S (15) Fritsche J (16) Gulde S (17) Hengler S (18) Hilf N (19) Hossain MB (20) Hukelmann J (21) Kalra M (22) Krishna D (23) Kursunel MA (24) Maurer D (25) Mayer-Mokler A (26) Mendrzyk R (27) Mohamed A (28) Pozo K (29) Satelli A (30) Letizia M (31) Schuster H (32) Schoor O (33) Wagner C (34) Rammensee HG (35) Reinhardt C (36) Singh-Jasuja H (37) Walter S (38) Weinschenk T (39) Luke JJ (40) Britten CM

Nature medicine

Wermke et al. reported interim data from a phase 1 dose-escalation trial of IMA203 – PRAME-directed autologous TCR T cell therapy – in HLA-A*02+ patients with PRAME+ recurrent and/or refractory solid tumors. Although the PRAME TCR was pairing-optimized and affinity-enhanced, IMA203 was safe and well tolerated, without any treatment-related fatalities. IMA203 rapidly engrafted tumors and demonstrated long-term persistence. In the 40 patients treated with IMA203, the unconfirmed/confirmed (u/c)ORR was 52.5%, and the cORR was 28.9%, with a median duration of response of 4.4 months. Higher PRAME expression and T cell infiltration correlated with deeper responses and longer PFS.

Contributed by Shishir Pant

ABSTRACT: In contrast to chimeric antigen receptor T cells, T cell receptor (TCR)-engineered T cells can target intracellular tumor-associated antigens crucial for treating solid tumors. However, most trials published so far show limited clinical activity. Here we report interim data from a first-in-human, multicenter, open-label, 3_+_3 dose-escalation/de-escalation phase 1 trial studying IMA203, an autologous preferentially expressed antigen in melanoma (PRAME)-directed TCR T cell therapy in HLA-A*02(+) patients with PRAME(+) recurrent and/or refractory solid tumors, including melanoma and sarcoma. Primary objectives include the evaluation of safety and tolerability and the determination of the maximum tolerated dose (MTD) and/or recommended dose for extension. Secondary objectives include the evaluation of IMA203 TCR-engineered T cell persistence in peripheral blood, tumor response as well as duration of response. A total of 27 patients were enrolled in the phase 1a dose escalation and 13 patients in the phase 1b dose extension. IMA203 T cells were safe, and the MTD was not reached. Of the 41 patients receiving treatment (that is, who started lymphodepletion), severe cytokine release syndrome was observed in 4.9% (2/41), and severe neurotoxicity did not occur. In the 40 patients treated with IMA203, an overall response rate consisting of patients with unconfirmed or confirmed response (u/cORR) of 52.5% (21/40) and a cORR of 28.9% (11/38) was observed with a median duration of response of 4.4_months (range, 2.4-23.0, 95% confidence interval: 2.6-not reached) across multiple indications. Rapid T cell engraftment and long-term persistence of IMA203 T cells were observed. IMA203 T cells trafficked to all organs, and confirmed responses were more frequent in patients with higher dose. T cell exhaustion was not observed in the periphery; deep responses were enriched at higher PRAME expression; and higher T cell infiltration resulted in longer progression-free survival. Overall, IMA203 showed promising anti-tumor activity in multiple solid tumors, including refractory melanoma. ClinicalTrials.gov identifier: NCT03686124 .

Author Info: (1) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. National Center for Tumor Diseases, Dresden, Germany. (2) Department of Sarcoma Me

Author Info: (1) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. National Center for Tumor Diseases, Dresden, Germany. (2) Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3) Comprehensive Cancer Center Mainfranken, University Hospital WŸrzburg, WŸrzburg, Germany. (4) Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (5) Department of Hematology, Oncology, Immunooncology, Stem Cell Transplantation, and Rheumatology, University Hospital Bonn, Bonn, Germany. (6) Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (7) Columbia University Medical Center, New York, NY, USA. (8) Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (9) Department of Oncology, Hematology, and Bone Marrow Transplantation with Section Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. (10) Department of Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany. (11) Department of Hematology, Oncology, Immunooncology, Stem Cell Transplantation, and Rheumatology, University Hospital Bonn, Bonn, Germany. (12) Immatics Biotechnologies GmbH, TŸbingen, Germany. (13) Immatics Biotechnologies GmbH, TŸbingen, Germany. (14) Immatics Biotechnologies GmbH, TŸbingen, Germany. (15) Immatics Biotechnologies GmbH, TŸbingen, Germany. (16) Immatics Biotechnologies GmbH, TŸbingen, Germany. (17) Immatics Biotechnologies GmbH, TŸbingen, Germany. (18) Immatics Biotechnologies GmbH, TŸbingen, Germany. (19) Immatics US, Inc., Houston, TX, USA. (20) Immatics Biotechnologies GmbH, TŸbingen, Germany. (21) Immatics US, Inc., Houston, TX, USA. (22) Immatics US, Inc., Houston, TX, USA. (23) Immatics Biotechnologies GmbH, TŸbingen, Germany. (24) Immatics Biotechnologies GmbH, TŸbingen, Germany. (25) Immatics Biotechnologies GmbH, TŸbingen, Germany. (26) Immatics Biotechnologies GmbH, TŸbingen, Germany. (27) Immatics US, Inc., Houston, TX, USA. (28) Immatics US, Inc., Houston, TX, USA. (29) Immatics US, Inc., Houston, TX, USA. (30) Immatics Biotechnologies GmbH, TŸbingen, Germany. (31) Immatics Biotechnologies GmbH, TŸbingen, Germany. (32) Immatics Biotechnologies GmbH, TŸbingen, Germany. (33) Immatics Biotechnologies GmbH, TŸbingen, Germany. (34) Institute of Immunology, Eberhard Karls University TŸbingen, TŸbingen, Germany. (35) Immatics Biotechnologies GmbH, TŸbingen, Germany. (36) Immatics Biotechnologies GmbH, TŸbingen, Germany. (37) Immatics US, Inc., Houston, TX, USA. (38) Immatics Biotechnologies GmbH, TŸbingen, Germany. (39) Cancer Immunotherapeutics Center, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA. (40) Immatics Biotechnologies GmbH, TŸbingen, Germany. cedrik.britten@immatics.com.

Citation: Nat Med 2025 Apr 9 Epub04/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40205198

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Immunotherapy with conventional type-1 dendritic cells induces immune memory and limits tumor relapse Spotlight 

(1) Heras-Murillo I (2) Mañanes D (3) Munné P (4) Núñez V (5) Herrera J (6) Catalá-Montoro M (7) Alvarez M (8) Del Pozo MA (9) Melero I (10) Wculek SK (11) Sancho D

Nature communications | Free PMC Article

Heras-Murillo et al. treated mice with tumor cell lysate-loaded syngeneic splenic selected cDC populations. cDC1-based vaccines induced cancer-specific Teff and Tmem cells, and reduced tumor burden in therapeutic and prophylactic settings more effectively than cDC2-based vaccines, even in hosts lacking cDC1s. cDC1-based treatment in adjuvant and neoadjuvant contexts prevented relapse better than anti-PD-1 therapy. Neoadjuvant cDC1-based therapy boosted tumor-infiltrating CD8+ and CD4+ T resident memory (Trm) cell numbers just prior to tumor remission. Greater CD4+ Trm-like cell abundance correlated with cDC1 presence in human tumors, and patient survival.

Contributed by Paula Hochman

(1) Heras-Murillo I (2) Mañanes D (3) Munné P (4) Núñez V (5) Herrera J (6) Catalá-Montoro M (7) Alvarez M (8) Del Pozo MA (9) Melero I (10) Wculek SK (11) Sancho D

Nature communications | Free PMC Article

Heras-Murillo et al. treated mice with tumor cell lysate-loaded syngeneic splenic selected cDC populations. cDC1-based vaccines induced cancer-specific Teff and Tmem cells, and reduced tumor burden in therapeutic and prophylactic settings more effectively than cDC2-based vaccines, even in hosts lacking cDC1s. cDC1-based treatment in adjuvant and neoadjuvant contexts prevented relapse better than anti-PD-1 therapy. Neoadjuvant cDC1-based therapy boosted tumor-infiltrating CD8+ and CD4+ T resident memory (Trm) cell numbers just prior to tumor remission. Greater CD4+ Trm-like cell abundance correlated with cDC1 presence in human tumors, and patient survival.

Contributed by Paula Hochman

ABSTRACT: The potential of dendritic cell (DC) vaccination against cancer is not fully achieved. Little is known about the precise nature of the anti-cancer immune response triggered by different natural DC subsets and their relevance in preventing postsurgical tumor recurrence. Here, we use mouse splenic conventional DC1s (cDC1s) or cDC2s pulsed with tumor cell lysates to generate DC vaccines. cDC1-based vaccination induces a stronger effector and memory CD4(+) and CD8(+) anti-tumor T cell response, leading to a better control of tumors treated either therapeutically or prophylactically. Using an experimental model of tumor relapse, we show that adjuvant or neoadjuvant cDC1 vaccination improves anti-tumor immune memory, particularly by increasing the infiltrates of CD4(+) tissue resident memory (Trm) and CD8(+) memory T cells. This translates into complete prevention of tumor relapses. Moreover, elevated abundance of cDC1s positively correlates with CD4(+) Trm presence, and both associate with enhanced survival in human breast cancer and melanoma. Our findings suggest that cDC1-based vaccination excels at immune memory induction and prevention of cancer recurrence.

Author Info: (1) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (2) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Universidad Aut—noma d

Author Info: (1) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (2) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Universidad Aut—noma de Madrid, Escuela de Doctorado, Madrid, Spain. (3) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (4) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (5) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (6) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (7) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. (8) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. (9) Program of Immunology and Immunotherapy, CIMA Universidad de Navarra, Pamplona, Spain. Navarra Institute for Health Research (IDISNA), Pamplona, Spain. Centro de Investigaci—n BiomŽdica en Red de C‡ncer (CIBERONC), Madrid, Spain. Nuffield Department of Medicine and Churchill Hospital. University of Oxford, Oxford, UK. (10) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. stefanie.wculek@irbbarcelona.org. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. stefanie.wculek@irbbarcelona.org. (11) Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. dsancho@cnic.es.

Citation: Nat Commun 2025 Apr 9 16:3369 Epub04/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40204706

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Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion

Spotlight 

(1) Zhu Y (2) Zhou Z (3) Du X (4) Lin X (5) Liang ZM (6) Chen S (7) Sun Y (8) Wang Y (9) Na Z (10) Wu Z (11) Zhong J (12) Han B (13) Zhu X (14) Fu W (15) Li H (16) Luo ML (17) Hu H

Cancer cell

Zhu et al. found that serum arginine increased during breast cancer progression and originated primarily from cancer epithelial cells, which expressed the arginine biosynthetic enzyme ASS1. Macrophage polyamines downstream of arginine signaling regulated TAM suppressive activity, and Ass1 KD in breast cancer cells inhibited tumor growth only in the presence of macrophages. Activity of spermine, a potent suppressive polyamine, was critically dependent on p53 signaling, which promoted demethylation of key genes, including PPARG by the enzyme TDG. In vivo, TDG KD inhibited TAM polarization and increased CD8+ T cell infiltration to promote tumor control.

Contributed by Morgan Janes

(1) Zhu Y (2) Zhou Z (3) Du X (4) Lin X (5) Liang ZM (6) Chen S (7) Sun Y (8) Wang Y (9) Na Z (10) Wu Z (11) Zhong J (12) Han B (13) Zhu X (14) Fu W (15) Li H (16) Luo ML (17) Hu H

Cancer cell

Zhu et al. found that serum arginine increased during breast cancer progression and originated primarily from cancer epithelial cells, which expressed the arginine biosynthetic enzyme ASS1. Macrophage polyamines downstream of arginine signaling regulated TAM suppressive activity, and Ass1 KD in breast cancer cells inhibited tumor growth only in the presence of macrophages. Activity of spermine, a potent suppressive polyamine, was critically dependent on p53 signaling, which promoted demethylation of key genes, including PPARG by the enzyme TDG. In vivo, TDG KD inhibited TAM polarization and increased CD8+ T cell infiltration to promote tumor control.

Contributed by Morgan Janes

ABSTRACT: Arginine metabolism reshapes the tumor microenvironment (TME) into a pro-tumor niche through complex metabolic cross-feeding among various cell types. However, the key intercellular metabolic communication that mediates the collective effects of arginine metabolism within the TME remains unclear. Here, we reveal that the metabolic interplay between cancer cells and macrophages plays a dominant role in arginine-driven breast cancer progression. Within the TME, breast cancer cells serve as the primary source of arginine, which induces a pro-tumor polarization of tumor-associated macrophages (TAMs), thereby suppressing the anti-tumor activity of CD8(+) T cells. Notably, this cancer cell-macrophage interaction overrides the arginine-mediated enhancement of CD8(+) T cell anti-tumor activity. Mechanistically, polyamines derived from arginine metabolism enhance pro-tumor TAM polarization via thymine DNA glycosylase (TDG)-mediated DNA demethylation, regulated by p53 signaling. Importantly, targeting the arginine-polyamine-TDG axis between cancer cells and macrophages significantly suppresses breast cancer growth, highlighting its therapeutic potential.

Author Info: (1) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Genetic Medicine, Dongguan Children's Hospital Affiliated

Author Info: (1) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Genetic Medicine, Dongguan Children's Hospital Affiliated to Guangdong Medical University, Dongguan, China. (2) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (3) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (4) Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou 515031, China. (5) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (6) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (7) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China; Experimental Research Center, Zhejiang Cancer Hospital, Hangzhou 310022, China. (8) Experimental Research Center, Zhejiang Cancer Hospital, Hangzhou 310022, China. (9) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China. (10) Diagnosis and Treatment Center of Breast Diseases, Shantou Central Hospital, Shantou 515031, China. (11) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (12) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (13) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (14) Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. (15) Hangzhou Institute of Medicine, Chinese Academy of Sciences, Zhejiang Cancer Hospital, Hangzhou 310018, China. Electronic address: lihongde@him.cas.cn. (16) Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China. Electronic address: luomli@mail.sysu.edu.cn. (17) Breast Cancer Center, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou 310022, China. Electronic address: huhai@zjcc.org.cn.

Citation: Cancer Cell 2025 Apr 1 Epub04/01/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40185095

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The local microenvironment suppresses the synergy between irradiation and anti-PD1 therapy in breast-to- brain metastasis

Spotlight 

(1) Wischnewski V (2) Guerrero Aruffo P (3) Massara M (4) Maas RR (5) Soukup K (6) Joyce JA

Cell reports

Wischnewski et al. demonstrated that CD8+ T cells infiltrated breast cancer brain metastases (BC-BrM), but failed to elicit an effective antitumor immune response, in contrast to genetically identical extracranial tumors. Brain irradiation transiently elevated the lymphoid-to-myeloid cell ratio in the BrM TME, and while it did not synergize with anti-PD-1 in the BrM, this combination did exhibit synergy in extracranial tumors, suggesting an immunosuppressive role of the brain-specific TME. Transcriptional and functional analyses identified neutrophils and TREM2-expressing macrophages as key mediators of local T cell suppression within the brain.

Contributed by Shishir Pant

(1) Wischnewski V (2) Guerrero Aruffo P (3) Massara M (4) Maas RR (5) Soukup K (6) Joyce JA

Cell reports

Wischnewski et al. demonstrated that CD8+ T cells infiltrated breast cancer brain metastases (BC-BrM), but failed to elicit an effective antitumor immune response, in contrast to genetically identical extracranial tumors. Brain irradiation transiently elevated the lymphoid-to-myeloid cell ratio in the BrM TME, and while it did not synergize with anti-PD-1 in the BrM, this combination did exhibit synergy in extracranial tumors, suggesting an immunosuppressive role of the brain-specific TME. Transcriptional and functional analyses identified neutrophils and TREM2-expressing macrophages as key mediators of local T cell suppression within the brain.

Contributed by Shishir Pant

ABSTRACT: The brain environment is uniquely specialized to protect its neuronal tissue from excessive inflammation by tightly regulating adaptive immunity. However, in the context of brain cancer progression, this regulation can lead to a conflict between T cell activation and suppression. Here, we show that, while CD8(+) T cells can infiltrate breast cancer-brain metastases, their anti-tumor cytotoxicity is locally suppressed in the brain. Conversely, CD8(+) T cells exhibited tumoricidal activity in extracranial mammary lesions originating from the same cancer cells. Consequently, combined high-dose irradiation and anti-programmed cell death protein 1 (PD1) therapy was effective in extracranial tumors but not intracranial lesions. Transcriptional analyses and functional studies identified neutrophils and Trem2-expressing macrophages as key sources for local T cell suppression within the brain, providing rational targets for future therapeutic strategies.

Author Info: (1) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agor

Author Info: (1) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. Electronic address: vladimir.wischnewski@tron-mainz.de. (2) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (3) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (4) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland; Neuroscience Research Center, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland; Department of Neurosurgery, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. (5) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland. (6) Department of Oncology, University of Lausanne, CH 1011 Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, CH 1011 Lausanne, Switzerland; Agora Cancer Research Centre Lausanne, CH 1011 Lausanne, Switzerland; Lundin Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, CH 1011 Lausanne, Switzerland. Electronic address: johanna.joyce@unil.ch.

Citation: Cell Rep 2025 Mar 25 44:115427 Epub03/17/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40106433

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Soluble CTLA-4 regulates immune homeostasis and promotes resolution of inflammation by suppressing type 1 but allowing type 2 immunity

Featured  

(1) Osaki M (2) Sakaguchi S

Immunity

Investigating the role of soluble CTLA-4 (sCTLA-4) versus membrane-bound CTLA-4 (mCTLA-4) Osaki and Sakaguchi found that sCTLA-4 plays a role in limiting autoimmunity though interactions with APCs, blocking CD80/86 and limiting the induction of type 1 immunity, while still allowing for the induction of type 2 immunity under chronic inflammatory conditions. In mouse models, sCTLA-4 was found to limit autoimmunity in colitis models and enhance wound healing, but also to limit antitumor immune responses.

(1) Osaki M (2) Sakaguchi S

Immunity

Investigating the role of soluble CTLA-4 (sCTLA-4) versus membrane-bound CTLA-4 (mCTLA-4) Osaki and Sakaguchi found that sCTLA-4 plays a role in limiting autoimmunity though interactions with APCs, blocking CD80/86 and limiting the induction of type 1 immunity, while still allowing for the induction of type 2 immunity under chronic inflammatory conditions. In mouse models, sCTLA-4 was found to limit autoimmunity in colitis models and enhance wound healing, but also to limit antitumor immune responses.

ABSTRACT: Cytotoxic T-lymphocyte-associated antigen -4 (CTLA-4) is a co-inhibitory receptor that restricts T cell activation. CTLA-4 exists as membrane (mCTLA-4) and soluble (sCTLA-4) forms, but the key producers, kinetics, and functions of sCTLA-4 are unclear. Here, we investigated the roles of sCTLA-4 in immune regulation under non-inflammatory and inflammatory conditions. Effector regulatory T (Treg) cells were the most active sCTLA-4 producers in basal and inflammatory states, with distinct kinetics upon T cell receptor (TCR) stimulation. We generated mice specifically deficient in sCTLA-4 production, which exhibited spontaneous activation of type 1 immune cells and heightened autoantibody/immunoglobulin E (IgE) production. Conversely, mCTLA-4-deficient mice developed severe type 2-skewed autoimmunity. sCTLA-4 blockade of CD80/86 on antigen-presenting cells inhibited T helper (Th)1, but not Th2, differentiation in vitro. In vivo, Treg-produced sCTLA-4, suppressed Th1-mediated experimental colitis, and enhanced wound healing but hampered tumor immunity. Thus, sCTLA-4 is essential for immune homeostasis and controlling type 1 immunity while allowing type 2 immunity to facilitate resolution in inflammatory conditions.

Author Info: (1) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute

Author Info: (1) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. (2) Laboratory of Experimental Immunology, WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan; Laboratory of Experimental Immunology, Institute for Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan. Electronic address: shimon@ifrec.osaka-u.ac.jp.

Citation: Immunity 2025 Apr 8 58:889-908.e13 Epub03/31/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40168991

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