Antibody-dependent cellular cytotoxicity (ADCC) in the anti-tumor effect of cetuximab in metastatic colorectal cancer (mCRC) is only based on the impact of FcγRIIIA (CD16) polymorphisms as predictive of therapeutic response. However, nature, density and therapeutic impact of FcγRIIIA (CD16) effector cells in tumor remain poorly documented. Moreover, the inhibition of cetuximab-mediated ADCC induced by NK cells by the engagement of the new inhibitory CD94-NKG2A immune checkpoint has only been demonstrated . This multicentric study aimed to determine, on paired primary and metastatic tissue samples from a cohort of mCRC patients treated with cetuximab: 1) the nature and density of FcγRIIIA (CD16) immune cells, 2) the expression profile of HLA-E/β2m by tumor cells as well as the density of CD94 immune cells and 3) their impact on both objective response to cetuximab and survival. We demonstrated that FcγRIIIA (CD16) intraepithelial immune cells mainly correspond to tumor-associated neutrophils (TAN), and their high density in metastases was significantly associated with a better response to cetuximab, independently of the expression of the CD94/NKG2A inhibitory immune checkpoint. However, HLA-E/β2m, preferentially overexpressed in metastases compared with primary tumors and associated with CD94 tumor infiltrating lymphocytes (TILs), was associated with a poor overall survival. Altogether, these results strongly support the use of bispecific antibodies directed against both EGFR and FcγRIIIA (CD16) in mCRC patients, to boost cetuximab-mediated ADCC in wild-type mCRC patients. The preferential overexpression of HLA-E/β2m in metastases, associated with CD94 TILs and responsible for a poor prognosis, provides convincing arguments to inhibit this new immune checkpoint with monalizumab, a humanized anti-NKG2A antibody, in combination with anti- FcγRIIIA/EGFR bispecific antibodies as a promising therapeutic perspective in wild-type mCRC patients.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239306 | PMC |
| http://dx.doi.org/10.3389/fonc.2021.684478 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis.
Sci Rep
January 2025
Department of Biological Sciences, Virginia Tech, Blacksburg, VA, 24061-0910, USA.
Sepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immunosuppression in sepsis survivors. This is due in part to immune dysfunction resulting from monocyte exhaustion, a phenotype of reduced antigen presentation, altered CD14/CD16 inflammatory subtypes, and disrupted cytokine production. Whereas previous research demonstrated improved sepsis survival in Ticam2 mice, the contribution of TICAM2 to long-term exhaustion memory remained unknown.
View Article and Find Full Text PDFInflammatory Monocyte Subsets Correlation with Iron Levels in Low Vitamin D Pediatric Transfusion-Dependent Thalassemia.
J Inflamm Res
January 2025
Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, 45363, Indonesia.
Background: Patients with transfusion-dependent thalassemia experience iron dysregulation, which affects the immune response. Surface proteins such as FcγRIII (CD16), lipopolysaccharide receptor (CD14), and human leukocyte antigen (HLA-DR) on monocytes are crucial for innate and adaptive responses. Blood monocytes, identified by their CD14 and CD16 expression, show functional diversity during injury or inflammation.
View Article and Find Full Text PDFArticle Synopsis
- FT596 is a novel cancer therapy using iPSC-derived CAR NK cells targeting CD19, designed to assess its safe dosage and effectiveness alone and with rituximab in patients with B-cell lymphoma.
- This phase 1 trial involved patients with relapsed or refractory B-cell lymphoma, administering FT596 after chemotherapy, with separate regimens for those receiving rituximab and those who did not.
- The study measured potential side effects while determining the optimal dose of FT596 and allowed modifications to the treatment based on patient tolerance and response.
Hydroxysafflor yellow A attenuates the inflammatory response in cerebral ischemia-reperfusion injured mice by regulating microglia polarization per SIRT1-mediated HMGB1/NF-κB signaling pathway.
Int Immunopharmacol
January 2025
Department of Pharmacy, Anhui University of Chinese Medicine, Hefei, China; Anhui Province Key Laboratory of Traditional Chinese Medicine Decoction Pieces of New Manufacturing Technology, Bozhou 236000, China. Electronic address:
Background: Hydroxysafflor yellow A (HSYA), an active component isolated from Carthamus tinctorius L., has demonstrated potent protective effects against cerebral ischaemia/reperfusion (I/R) injury. Microglial polarisation plays a crucial role in I/R.
View Article and Find Full Text PDFFT538, iPSC-derived NK cells, enhance AML cell killing when combined with chemotherapy.
J Cell Mol Med
January 2025
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Induced pluripotent stem cell (iPSC)-derived natural killer (NK) cells offer an opportunity for a standardized, off-the-shelf treatment with the potential to treat a wider population of acute myeloid leukaemia (AML) patients than the current standard of care. FT538 iPSC-NKs express a high-affinity, noncleavable CD16 to maximize antibody dependent cellular cytotoxicity, a CD38 knockout to improve metabolic fitness, and an IL-15/IL-15 receptor fusion preventing the need for cytokine administration, the main source of adverse effects in NK cell-based therapies. Here, we sought to evaluate the potential of FT538 iPSC-NKs as a therapy for AML through their effect on AML cell lines and primary AML cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!