AACR 2023 Poster 5118

STING Agonist and TLR7/8 Agonist Overcame Anti-PD-1 Resistance Mediated by Loss of β2M

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.

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• Methods for generating a MC38-OVA-β2M KO tumor model
  
  
• Expression and function data for MHC-I in MC38-OVA-β2M KO cells
  
  
• Evaluation of STING Agonist and TLR7/8 Agonist in overcoming PD-1 blockade resistance in the MC38-OVA-β2M KO tumor model

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