FcγRIIB is a T cell checkpoint in antitumor immunity

Farley, Clara R.; Morris, Anna B.; Tariq, Marvi; Bennion, Kelsey B.; Potdar, Sayalee; Kudchadkar, Ragini R.; Lowe, Michael C.; Ford, Mandy L.

doi:10.1172/jci.insight.135623

Cited by 16 publications

(22 citation statements)

References 34 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 27 36 While naïve T cells do not express FcγRs, subsets of activated CD4+ T cells may express FcγRIIIa, FcγRIIa, and FcγRIIb, 39 40 and subsets of activated memory CD8+ T cells may express FcγRIIb. 41 CD56+ (neural cell adhesion molecule) subsets of CD3+ T cells express FcγRs and are capable of mediating ADCC, such as NK T cells expressing FcγRIIIa and γδ T cells expressing FcγRIIa and FcγRIIIa. 24 These small subsets of FcγR-expressing T cells potentially could influence the linkage between innate and adaptive immunity.…”

Section: Introductionmentioning

confidence: 99%

Role of Fcγ receptors in HER2-targeted breast cancer therapy

Musolino

Gradishar

Rugo

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)–dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell–mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms.

show abstract

Section: Introductionmentioning

confidence: 99%

Role of Fcγ receptors in HER2-targeted breast cancer therapy

Musolino

Gradishar

Rugo

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…In addition, FCGR2B on malignant B-cells has been found to advance the internalization of targeting monoclonal antibodies, counteracting their capacity to generate antibody-dependent cellular cytotoxicity and thus diminishing their therapeutic efficacy [ 46 ]. Interestingly, in a melanoma mouse model, FCGR2B has been demonstrated to be upregulated in tumor-infiltrating CD8+ T-cells hampering their antitumor efficacy [ 47 ]. In the same study, it was also shown that CD8+ T-cells in melanoma patients express FCGR2B , proposing its role in down-regulating tumor-directed immune responses in humans.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy-Related Gene Signature in Prostate Cancer

Fortis

Goulielmaki

Aubert

et al. 2022

Cancers

View full text Add to dashboard Cite

Radiotherapy for localized prostate cancer has increased the cure and survival rates of patients. Besides its local tumoricidal effects, ionizing radiation has been linked to mechanisms leading to systemic immune activation, a phenomenon called the abscopal effect. In this study, we performed gene expression analysis on peripheral blood from prostate cancer patients obtained post- radiotherapy and showed that 6 genes, including CCR7, FCGR2B, BTLA, CD6, CD3D, and CD3E, were down-regulated by a range of 1.5–2.5-fold as compared to pre-radiotherapy samples. The expression of the signature consisting of these six genes was also significantly lower post- vs. pre-radiotherapy. These genes are involved in various tumor-promoting immune pathways and their down-regulation post-radiotherapy could be considered beneficial for patients. This is supported by the fact that low mRNA expression levels for the 6-gene signature in the prostate tumor tissue was linked to better survival. Importantly, we report that this 6-gene signature strongly correlated with a favorable prognosis regardless of poor standard clinicopathological parameters (i.e., Gleason score ≥ 8 and T3 (including T3a and T3b). Our pioneering data open the possibility that the 6-gene signature identified herein may have a predictive value, but this requires further long-term studies.

show abstract

“…Required bound better to IgG4P was FcγRIIb/c, which may play a role in suppressing tumour-infiltrating CD8 + T cells (Farley et al, 2021). Furthermore, glycosylation profile had an impact on IgG4P ICIs-ICIs with core plant α1,3-fucose and β1,2-xylose having lower affinity to FcγRIIa, FcγRIIb/c and FcγRIIIa.…”

Section: Discussionmentioning

confidence: 99%

Killer to cure: Expression and production costs calculation of tobacco plant‐made cancer‐immune checkpoint inhibitors

Ridgley

Finardi

Gengenbach

et al. 2023

Plant Biotechnology Journal

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICIs) have achieved huge clinical success.However, many still have limited response rates, and are prohibitively costly. There is a need for effective and affordable ICIs, as well as local manufacturing capacity to improve accessibility, especially to low-to-middle income countries (LMICs). Here, we have successfully expressed three key ICIs (anti-PD-1 Nivolumab, anti-NKG2A Monalizumab, and anti-LAG-3 Relatimab) transiently in Nicotiana benthamiana and Nicotiana tabacum plants. The ICIs were expressed with a combination of different Fc regions and glycosylation profiles. They were characterised in terms of protein accumulation levels, target cell binding, binding to human neonatal Fc receptors (hFcRn), human complement component C1q (hC1q) and various Fcγ receptors, as well as protein recovery during purification at 100 mg-and kg-scale. It was found that all ICIs bound to the expected target cells. Furthermore, the recovery during purification, as well as Fcγ receptor binding, can be altered depending on the Fc region used and the glycosylation profiles. This opens the possibility of using these two parameters to fine tune the ICIs for desired effector functions. A scenario-based production cost model was also generated based on two production scenarios in hypothetical high-and low-income countries. We have shown that the product accumulation and recovery of plant production platforms were as competitive as mammalian cell-based platforms. This highlights the potential of plants to deliver ICIs that are more affordable and accessible to a widespread market, including LMICs.

show abstract

FcγRIIB is a T cell checkpoint in antitumor immunity

Cited by 16 publications

References 34 publications

Role of Fcγ receptors in HER2-targeted breast cancer therapy

Role of Fcγ receptors in HER2-targeted breast cancer therapy

Radiotherapy-Related Gene Signature in Prostate Cancer

Killer to cure: Expression and production costs calculation of tobacco plant‐made cancer‐immune checkpoint inhibitors

Contact Info

Product

Resources

About