Fc gamma receptor binding modulates IgG clearance in cancer cachexia

Area of Science:

• Immunology
• Pharmacokinetics
• Oncology

Background:

• Cancer cachexia is associated with resistance to Immune Checkpoint Inhibitor (ICI) therapy.
• Patients with cancer cachexia exhibit elevated catabolic clearance (CL) of ICIs, a prognostic survival indicator.
• Fc-Gamma Receptors (FcγRs) influence ICI efficacy by binding the Fc portion of antibodies.

Purpose of the Study:

• To investigate the role of FcγRs in the catabolic clearance of human IgG1 (hIgG1) in a murine model of cancer cachexia.
• To compare the pharmacokinetic profiles of hIgG1 and a FcγR-binding deficient mutant (D265A) in tumor-bearing and tumor-free mice.

Main Methods:

• Pharmacokinetic studies of hIgG1 and D265A mutant in Lewis Lung Carcinoma (LLC) tumor-bearing (TB) and tumor-free (TF) mice.
• Immunofluorescence to detect and localize infused hIgG1 in mouse liver, focusing on FcγRIIb expression.
• Utilized FcγRIIb knockout mice to assess the impact of FcγRIIb on hIgG1 clearance.

Main Results:

• Catabolic clearance (CL) of both hIgG1 and D265A increased in LLC TB mice compared to TF controls.
• D265A mutant showed significantly lower CL than hIgG1 in LLC TB mice, indicating FcγR involvement.
• hIgG1 colocalized with FcγRIIb in liver sinusoidal endothelial cells (LSEC) in LLC TB mice; however, whole-body FcγRIIb knockout did not affect hIgG1 CL.

Conclusions:

• FcγRs play a role in the catabolic clearance of IgG antibodies in the context of LLC tumors and cancer cachexia.
• Altered FcγR expression or function in LLC tumors significantly impacts antibody CL.
• The observed increase in antibody CL is likely mediated by FcγRs beyond FcγRIIb, highlighting the importance of other FcγRs in cachexia.