CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success?

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Front. Med.

2022, Vol. 16

Issue (3) : 322-338 https://doi.org/10.1007/s11684-021-0901-2

REVIEW

CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success?

Pooria Safarzadeh Kozani¹, Pouya Safarzadeh Kozani², Fatemeh Rahbarizadeh^1,³(

)

¹. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, P.O. Box 14115/111, Iran
². Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, P.O. Box 44771/66595, Iran
³. Research and Development Center of Biotechnology, Tarbiat Modares University, Tehran, P.O. Box 14115/111, Iran

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Abstract

Immune-based therapies have experienced a pronounced breakthrough in the past decades as they acquired multiple US Food and Drug Administration (FDA) approvals for various indications. To date, six chimeric antigen receptor T cell (CAR-T) therapies have been permitted for the treatment of certain patients with relapsed/refractory hematologic malignancies. However, several clinical trials of solid tumor CAR-T therapies were prematurely terminated, or they reported life-threatening treatment-related damages to healthy tissues. The simultaneous expression of target antigens by healthy organs and tumor cells is partly responsible for such toxicities. Alongside targeting tumor-specific antigens, targeting the aberrantly glycosylated glycoforms of tumor-associated antigens can also minimize the off-tumor effects of CAR-T therapies. Tn, T, and sialyl-Tn antigens have been reported to be involved in tumor progression and metastasis, and their expression results from the dysregulation of a series of glycosyltransferases and the endoplasmic reticulum protein chaperone, Cosmc. Moreover, these glycoforms have been associated with various types of cancers, including prostate, breast, colon, gastric, and lung cancers. Here, we discuss how underglycosylated antigens emerge and then detail the latest advances in the development of CAR-T-based immunotherapies that target some of such antigens.

Keywords cancer immunotherapy chimeric antigen receptor solid tumors tumor-associated antigen glycosylation O-glycans adoptive cell therapy

Corresponding Author(s): Fatemeh Rahbarizadeh

Just Accepted Date: 15 April 2022 Online First Date: 10 June 2022 Issue Date: 18 July 2022

Cite this article:

Pooria Safarzadeh Kozani,Pouya Safarzadeh Kozani,Fatemeh Rahbarizadeh. CAR T cells redirected against tumor-specific antigen glycoforms: can low-sugar antigens guarantee a sweet success?[J]. Front. Med., 2022, 16(3): 322-338.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0901-2
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I3/322

Fig.1 Anatomy of a conventional CAR construct and action mechanism of a CAR-T. (A) Different components used in the construction of a second-generation CAR molecule. (B) The mechanism by which CAR-Ts enforce cytolytic reactions against the target tumor cells. Upon target antigen encounter, the downstream signaling cascades of the costimulatory domain(s) and the activation domain are triggered and result in the CAR-T-mediated production and secretion of granzyme and perforin. The downstream signaling of CD3ζ, 4-1BB, and CD28 is dependent on ZAP70, NF-κB, and PI3K, respectively. CAR-T, chimeric antigen receptor T-cell; ICOS, inducible T-cell costimulator; KIR2DS2, killer cell immunoglobulin-like receptor 2DS2; NF-κB, nuclear factor-κB; PI3K, phosphoinositide 3-kinase; ZAP70, the ζ-associated protein of 70 kDa.

Fig.2 Structural differences between properly glycosylated and aberrantly glycosylated forms of an antigen. The cancer-associated glycoform of the antigen exhibits a substantially different structural conformation compared with the one expressed on the surface of the normal cell. As “form is function”, Tn, T, and sialyl-Tn antigens are expected to be functionally different from their normal counterparts. This altered 3D conformation might impinge on the stability and expression level of the antigen, as well as its turnover.

Fig.3 Underlying mechanism of the emergence of Tn, T, and/or sialyl-Tn antigens. In normal situations (left panel), the Cosmc complex helps the unfolded T-synthase fold and assemble properly by serving as an endoplasmic reticulum chaperone. Once properly folded, the active T-synthase dimer exits the endoplasmic reticulum and enters the Golgi where it plays a critical role in the O-glycosylation of glycoproteins. In some tumor cells (right panel), somatic mutations or epigenetic gene silencing, such as those induced by hypoxia, can lead to Cosmc deficiency, which results in the aggregation of unfolded T-synthase, its proteolytic cleavage and retrotranslocation into the cytosol, and its polyubiquitination and consequent degradation. The loss of functional T-synthase, which might also be caused by some undeciphered mechanisms as detailed before, gives rise to the aberrant O-glycosylation of proteins and the surface expression of Tn, T, and sialyl-Tn antigens. In the case of sialyl-Tn antigen, a Neu5Ac may also be added to Tn antigen by ST6GalNAc-I, which results in the formation of sialyl-Tn antigen [36]. The aberrant expression of sialyl-Tn antigen is also speculated to be a result of the suppressive effects of ST6GalNAc-I on the functionality of T-synthase because of the high-level expression of ST6GalNAc-I [36]. ER, endoplasmic reticulum.

Fig.4 Underlying mechanism of how incorporating a targeting domain that only binds the tumor-specific glycoform of an antigen into the CAR construct considerably diminishes the “on-target, off-tumor” toxicities of CAR-Ts. The CAR represented here only recognizes the Tn, T, or sialyl-Tn glycoform of the target antigen, which is restricted to tumor cells. Such CAR-Ts are unable to enforce tumoricidal reactions toward healthy cells expressing the properly glycosylated form of the antigen because they cannot engage with them. CAR-T, chimeric antigen receptor T cell.

Tab.1 Summary of various CasMabs specific for tumor-specific antigen glycoforms

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