Avelumab induces superior Fc-Fc receptor-dependent natural killer cell stimulation and dendritic cell cross-talk compared to durvalumab

Natural killer cells and dendritic cells are instrumental in controlling cancer. However, the impact of PD-L1 blockade therapy on these immune cell types is not well understood. Furthermore, across many clinical trials, different anti-PD-L1 antibodies have produced varying levels of efficacy in patients, and the basis of these differences are obscure. Avelumab, a native Fc IgG1 antibody, and durvalumab, a mutant-Fc IgG1 antibody, are two of the most commonly used anti-PD-L1 agents for cancer immunotherapy. We compared the mechanistic effects of these agents. Our study shows the robust impact of Fc-signaling on NK cells by avelumab. In contrast, durvalumab failed to induce NK cell activation or promote NK-DC cross-talk. Overall design: We investigated impact of two PD-L1 inhibitors (avelumab and durvulumab) in (1) PCI-15B tumor cells, (2) NK+PCI-15B coculture, and (3) NK+DC+PCI-15B coculture. Each treatment group has data in triplicates. We performed differential gene expression analysis and GSEA to show the differences between two groups. Normalized data was used to show differences. In condition (1) PCI-15B tumor cells differences were identified between any two groups: no_ab_1, no_ab_2, no_ab_3; Durva_1, Durva_2, Durva_3; Ave_1, Ave_2, Ave_3. In condition (2) NK+PCI-15B coculture differences were identified between two groups: No_ab_1, No_ab_2, No_ab_3; NK_Durva_1, NK_Durva_2, NK_Durva_3. In condition (3) NK+DC+PCI-15B coculture differences were identified between two groups: R20001_IgG1, R20001_IgG2, R20001_IgG3; R20002_Durv_1, R20002_Durv_2, R20002_Durv_3.