Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade

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.

Targeting Post-Translational Modifications to Improve Combinatorial Therapies in Breast Cancer: The Role of Fucosylation

“…As a result, mice transplanted with Fut8 KO hematopoietic bone marrow displayed enhanced resistance to inflammation [ 71 ]. In addition, macrophages represent one the largest leukocyte population in various tumor microenvironments and have been described to display unusual glycosylation patterns, which have, in turn, been proposed as potential therapeutic targets [ 72 , 73 , 74 , 75 ].…”

Live‐Cell Glycocalyx Engineering

“…[67] Recently, therapeutic desialylation using an antibody-sialidase conjugate represents an immunotherapeutic approach to reshape macrophage phenotypes and augment the adaptive antitumor immune response. [68] By combining both tools of sialidase and sialylation inhibitor, O'Dwyer et al observed a better efficacy of NK cells against multiple myeloma. [26] Besides that, sLe X epitopes modulate the leukocyte homing, and some GBPs, such as Siglec-7/15 [69] and galectin-1/3, [70] are newly identified as immune checkpoints and have driven immense attention to improving ACT therapeutic efficacy.…”

“…Recombinant sialidase and trastuzumab conjugates were developed to selectively desialylate the human epidermal growth factor receptor 2 (HER2)‐positive tumor cells, which increased the susceptibility of cancer cells and ADCC [67] . Recently, therapeutic desialylation using an antibody‐sialidase conjugate represents an immunotherapeutic approach to reshape macrophage phenotypes and augment the adaptive antitumor immune response [68] . By combining both tools of sialidase and sialylation inhibitor, O′Dwyer et al.…”

Green approaches for extraction, chemical modification and processing of marine polysaccharides for biomedical applications

“…The application of AAC chemistry in polysaccharides has contributed to generate complex glycoconjugates that allowed the development of new biomaterials exhibiting improved properties and functions (Elchinger et al, 2011), assuring high yields and highly selective products by carbon-hetero bond formation reactions, which results in the formation of a triazole ring unit (Tan et al, 2018). On the other hand, it is (Cioce et al, 2022;Stanczak et al, 2022).…”

“…In this scope, we highlight the recent Nobel Prize in Chemistry in which Carolyn Bertozzi has applied such elegant and efficient chemical reaction inside living organisms, without disrupting the normal cell chemistry. Such development has leveraged click chemistry to a new dimension, affording to map cells and track biological processes as well as to improve the targeting of cancer pharmaceuticals ( Cioce et al, 2022 ; Stanczak et al, 2022 ).…”