Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma

Anderson, Georgina; Ballester-Beltrán, José; Giotopoulos, George; Guerrero, José Antonio López; Surget, Sylvanie; Williamson, James C; So, Tsz; Bloxham, David; Aubareda, Anna; Asby, Ryan; Walker, I. R.; Jenkinson, Lesley; Soilleux, Elizabeth; Roy, James P; Teodósio, Ana; Ficken, Catherine; Officer, Leah; Nasser, Sara; Skerget, Sheri; Greaves, Peter; Tai, Yu‐Tzu; Anderson, Kenneth C.; MacFarlane, Marion; Thaventhiran, James; Huntly, Brian J. P.; Lehner, Paul J.; Chapman, Michael A.

doi:10.1182/blood.2021015161

Cited by 21 publications

(16 citation statements)

References 26 publications

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“…SEMA4A is a new target for MM and is expressed at a greater level on MM cells than BCMA and SLAMF7. SEM4A is rapidly internalized, displays a low level of shedding and appears essential for MM survival, making it unlikely to be genetically eliminated ( 68 ).…”

Section: Alternative Antigenic Proteins For Car T-cells To Target In ...mentioning

confidence: 99%

Road testing new CAR design strategies in multiple myeloma

et al. 2022

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A deeper understanding of basic immunology principles and advances in bioengineering have accelerated the mass production of genetically-reprogrammed T-cells as living drugs to treat human diseases. Autologous and allogeneic cytotoxic T-cells have been weaponized to brandish MHC-independent chimeric antigen receptors (CAR) that specifically engage antigenic regions on tumor cells. Two distinct CAR-based therapeutics designed to target BCMA are now FDA-approved based upon robust, sustained responses in heavily-pretreated multiple myeloma (MM) patients enrolled on the KarMMa and CARTITUDE-1 studies. While promising, CAR T-cells present unique challenges such as antigen escape and T-cell exhaustion. Here, we review novel strategies to design CARs that overcome current limitations. Co-stimulatory signaling regions were added to second-generation CARs to promote IL-2 synthesis, activate T-cells and preclude apoptosis. Third-generation CARs are composed of multiple co-stimulatory signaling units, e.g., CD28, OX40, 4-1BB, to reduce exhaustion. Typically, CAR T-cells incorporate a potent constitutive promoter that maximizes long-term CAR expression but extended CAR activation may also promote T-cell exhaustion. Hypoxia-inducible elements can be incorporated to conditionally drive CAR expression and selectively target MM cells within bone marrow. CAR T-cell survival and activity is further realized by blocking intrinsic regulators of T-cell inactivation. T-Cells Redirected for Universal Cytokine Killing (TRUCKs) bind a specific tumor antigen and produce cytokines to recruit endogenous immune cells. Suicide genes have been engineered into CAR T-cells given the potential for long-term on-target, off-tumor effects. Universal allo-CAR T-cells represent an off-the-shelf source, while logic-gated CAR T-cells are designed to recognize tumor-specific features coupled with Boolean-generated binary gates that then dictate cell-fate decisions. Future generations of CARs should further revitalize immune responses, enhance tumor specificity and reimagine strategies to treat myeloma and other cancers.

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Section: Alternative Antigenic Proteins For Car T-cells To Target In ...mentioning

confidence: 99%

Road testing new CAR design strategies in multiple myeloma

et al. 2022

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“…Sema4A was identified as a novel therapeutic target of myeloma. 41 Targeting Sema4A using an antibodydrug conjugate potently and selectively eradicated myeloma cells in vitro and in vivo. Sema4A conferred drug resistance on hepatocellular carcinoma by inducing the epithelial-mesenchymal transition (EMT).…”

Section: Sema4a In Cancermentioning

confidence: 99%

“…Sema4A was identified as a novel therapeutic target of myeloma 41 . Targeting Sema4A using an antibody‐drug conjugate potently and selectively eradicated myeloma cells in vitro and in vivo.…”

Section: Semaphorins In Pathogenesismentioning

confidence: 99%

Class IV semaphorins in disease pathogenesis

Nojima

2022

Pathology International

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Semaphorins are a large family of secreted and/or transmembrane proteins, originally identified as proteins that function in axon guidance during neuronal development. However, semaphorins play crucial roles in other physiological and pathological processes, including immune responses, angiogenesis, maintenance of tissue homeostasis, and cancer progression. Class IV semaphorins may be present as transmembrane and soluble forms and are implicated in the pathogenesis of various diseases. This review discusses recent progress on the roles of class IV semaphorins determined by clinical and experimental pathology studies.

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“…Cancer immunotherapy can easily target cell surface proteins as they are easily accessible, but finding effective targets is still challenging [14]. Literature studies indicate that Sema4A, acting as a biomarker for dendritic cell activation status and CTL stimulator, promotes the production of IFN-γ and inhibits tumour growth [15,16].…”

Section: Introductionmentioning

confidence: 99%

Design of a potential Sema4A-based multi-epitope vaccine to combat triple-negative breast cancer: an immunoinformatic approach

Paranthaman

Shanthi

2023

Med Oncol

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Immunotherapy is revamping the therapeutic strategies for TNBC owing to its higher mutational burden and tumour-associated antigens. One of the most intriguing developments in cancer immunotherapy is the focus on peptide-based cancer vaccines. Thus, the current work aims to develop an efficient peptide-based vaccine against TNBC that targets Sema4A, which has recently been identified as a major regulator of TNBC progression. Initially, the antigenic peptides derived from Sema4A were determined and evaluated based on their capability to provoke immunological responses. The assessed epitopes were then linked with a suitable adjuvant (RpfB and RpfE) and appropriate linkers (AAY, GPGPG, KK and EAAAK) to preclude junctional immunogenicity. Eventually, docking and dynamics simulations are performed against TLR-2, TLR-4, TLR-7 and TLR-9 to assess the interaction between the vaccine construct and TLR receptors, as the TLR signalling pathway is critical in the host immune response. The developed vaccine was then exposed to in silico cloning and immune simulation analysis. The findings suggest that the designed vaccine could potentially evoke significant humoral and cellular immune responses in the intended organism. Considering these outcomes, the final multi-epitope vaccine could be employed to serve as an effective choice for TNBC management and may open new avenues for further studies.

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Unbiased cell surface proteomics identifies SEMA4A as an effective immunotherapy target for myeloma

Cited by 21 publications

References 26 publications

Road testing new CAR design strategies in multiple myeloma

Road testing new CAR design strategies in multiple myeloma

Class IV semaphorins in disease pathogenesis

Design of a potential Sema4A-based multi-epitope vaccine to combat triple-negative breast cancer: an immunoinformatic approach

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