Aaron Li Hua, Chenpan Nie, Jie Lin, Annie Xiaoyu An, Ludovic Bourre, Jessie JingJing Wang
Crown Bioscience Inc., 16550 West Bernardo Drive, Building 5, Suite 525, San Diego, CA 92127
PD-1 blockade has achieved great success in the clinic. However, only a small subset of patients benefit from the treatment and most responders develop acquired resistance thereafter. One of the resistance mechanisms is beta-2-microglobulin (β2M) mutation mediated dysfunction of MHC-I antigen presentation, which contributes to attenuation of cellular cytotoxicity triggered by adaptive CD8+ T cells. Activating innate immunity, such as natural killer (NK) cells, can be used as a strategy to circumvent the attenuation. Immune-stimulating agents like stimulator of interferon genes (STING) agonists and Toll-like receptor (TLR) 7/8 agonists can elicit NK cell-mediated tumor rejection in preclinical tumor models, independent of CD8+ T cells. Thus, to evaluate novel therapeutic strategies overcoming anti-PD-1 resistance, a MC38-OVA-β2M KO tumor model was established.