Ribas et al. 2020 shows that melanoma PDLi responders have higher levels of pre-treatment HLA gene expr. in bulk tumor RNA relative to non-responders, with the difference being amplified upon treatment. Suggests a positive feedback loop exists, where PDL1i 'unlocks' T-cells (1/n)

to receive stimuli and in turn, upon stimuli (antigen presentation), T-cells release cytokines that lower immunosuppression in TME, leading to greater antigen presentation. This also suggests that in order to respond to PDL1i, patients need a basal amount of antigen pres. (2/n)

If they have this, then PDL1i can unlock the positive feedback loop that supercharges anti-tumor immunity. However, many patients simply do not have enough antigen pres. occurring in TME to start this cascade upon PL1i. Interesting study (Tsao et al. 2019) shows that CD47 (3/n)

blockade combined with Her2-IgG2 in Her2+ xenografts turns on HLA gene expression in M1 and M2 TME macrophages (single-cell RNA-seq). Suggests blocking CD47 while providing an FC receptor activating signal produces the transcriptome changes that sensitize patients to PDL1i (4/n)

Key question for $TRIL moving forward, is whether/to what extent 621 or 622 can provide enough CD47 inhibition in tandem with IgG activating signal to turn on HLA gene expression in the TME across heterogeneous immunosuppressive environments in solid tumors (5/5).