ICAM-1 Is Overexpressed by Cancers and Negatively Impacts Antibody-Based Therapies Including Antibody-Drug Conjugates

Humoral immunity utilizes antibodies and immune effector cells to mediate dysregulated cancer cell killing. These mechanisms are referred to as Humoral Immuno-Oncology (HIO). HIO immunosuppression is mediated by tumor-produced proteins called HIO factors. Using a combination of patient serum analysis and literature searches, we screened a number of samples to determine if they suppressed HIO. Herein, we identified that ICAM-1 (intercellular adhesion molecule 1) can bind IgG1-type antibodies and suppress their immune effector activity. Through a series of mutagenesis, we identified a unique motif within the IgG1CH3 domain essential for ICAM-1 binding, which inhibits antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Conservative amino acid substitutions within the CH3 domain were able to abrogate ICAM-1 binding and overcome ICAM-1 mediated immune effector suppression. Additionally, isogenic tumor cell lines with silenced ICAM-1 expression were more susceptible to antibody-drug conjugate (ADCs) cytotoxicity than parental cells. This effect appeared to correlate with membrane ICAM-1 binding to the IgG1 component that reduced ADC internalization, a function important for maximal target cell killing. These findings highlight a novel mechanism by which tumors can suppress the host's immune system for survival and offer new concepts for engineering antibody-based therapeutics that are refractory to ICAM-1 immunosuppression.