(1) Stanczak MA (2) Rodrigues Mantuano N (3) Kirchhammer N (4) Sanin DE (5) Jacob F (6) Coelho R (7) Everest-Dass AV (8) Wang J (9) Trefny MP (10) Monaco G (11) Bärenwaldt A (12) Gray MA (13) Petrone A (14) Kashyap AS (15) Glatz K (16) Kasenda B (17) Normington K (18) Broderick J (19) Peng L (20) Pearce OMT (21) Pearce EL (22) Bertozzi CR (23) Zippelius A (24) Läubli H
Stanczak et al. showed that hypersialylation on tumor cells promotes polarization of TAMs towards an immunosuppressive phenotype through interactions with Siglec-E, contributing to disease progression and immune escape. Genetic and therapeutic targeting of the sialoglycan-Siglec axis, either through desialylation or targeted removal of Siglec-E, promoted the repolarization of TAMs and supported stronger antitumor immune responses, particularly in the setting of immune checkpoint blockade. These results support further investigation of therapeutic desialylation as a potential immunotherapy.
(1) Stanczak MA (2) Rodrigues Mantuano N (3) Kirchhammer N (4) Sanin DE (5) Jacob F (6) Coelho R (7) Everest-Dass AV (8) Wang J (9) Trefny MP (10) Monaco G (11) Bärenwaldt A (12) Gray MA (13) Petrone A (14) Kashyap AS (15) Glatz K (16) Kasenda B (17) Normington K (18) Broderick J (19) Peng L (20) Pearce OMT (21) Pearce EL (22) Bertozzi CR (23) Zippelius A (24) Läubli H
Stanczak et al. showed that hypersialylation on tumor cells promotes polarization of TAMs towards an immunosuppressive phenotype through interactions with Siglec-E, contributing to disease progression and immune escape. Genetic and therapeutic targeting of the sialoglycan-Siglec axis, either through desialylation or targeted removal of Siglec-E, promoted the repolarization of TAMs and supported stronger antitumor immune responses, particularly in the setting of immune checkpoint blockade. These results support further investigation of therapeutic desialylation as a potential immunotherapy.
ABSTRACT: Immune checkpoint blockade (ICB) has substantially improved the prognosis of patients with cancer, but the majority experiences limited benefit, supporting the need for new therapeutic approaches. Up-regulation of sialic acid-containing glycans, termed hypersialylation, is a common feature of cancer-associated glycosylation, driving disease progression and immune escape through the engagement of Siglec receptors on tumor-infiltrating immune cells. Here, we show that tumor sialylation correlates with distinct immune states and reduced survival in human cancers. The targeted removal of Siglec ligands in the tumor microenvironment, using an antibody-sialidase conjugate, enhanced antitumor immunity and halted tumor progression in several murine models. Using single-cell RNA sequencing, we revealed that desialylation repolarized tumor-associated macrophages (TAMs). We also identified Siglec-E as the main receptor for hypersialylation on TAMs. Last, we found that genetic and therapeutic desialylation, as well as loss of Siglec-E, enhanced the efficacy of ICB. Thus, therapeutic desialylation represents an immunotherapeutic approach to reshape macrophage phenotypes and augment the adaptive antitumor immune response.
Author Info:
(1) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore
, MD 21287, USA. Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. (2) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (3) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (4) Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. (5) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (6) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (7) Institute for Glycomics, Griffith University, Gold Coast Campus, Gold Coast QLD4222, Australia. (8) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (9) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (10) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (11) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (12) Department of Chemistry, Stanford ChEM-H, and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. (13) Palleon Pharmaceuticals, Waltham, MA 02451, USA. (14) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. (15) Institute of Pathology, University Hospital Basel, 4031 Basel, Switzerland. (16) Division of Oncology, Department of Theragnostics, University Hospital Basel, 4031 Basel, Switzerland. (17) Palleon Pharmaceuticals, Waltham, MA 02451, USA. (18) Palleon Pharmaceuticals, Waltham, MA 02451, USA. (19) Palleon Pharmaceuticals, Waltham, MA 02451, USA. (20) Centre for Tumour Microenvironment, Barts Cancer Institute, Queen Mary University, London EC1M 6BQ, UK. (21) Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD 21287, USA. Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany. (22) Department of Chemistry, Stanford ChEM-H, and Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. (23) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. Division of Oncology, Department of Theragnostics, University Hospital Basel, 4031 Basel, Switzerland. (24) Department of Biomedicine, University Hospital and University of Basel, 4031 Basel, Switzerland. Division of Oncology, Department of Theragnostics, University Hospital Basel, 4031 Basel, Switzerland.
Citation: Sci Transl Med 2022 Nov 2 14:eabj1270 Epub11/02/2022
