An organoid co-culture model for probing systemic anti-tumor immunity in lung cancer

Deciphering the interactions between tumor micro- and systemic immune macro-environment is essential for developing more effective cancer diagnosis and treatment strategies. Here, we established a gel-liquid interface (GLI) co-culture of lung cancer organoids (LCOs) and paired peripheral blood mononuclear cells (PBMCs), featuring with enhanced interactions of immune cells and tumor organoids, to mimic the in vivo systemic anti-tumor immunity induced by immune checkpoint inhibitors (ICI). The co-culture model recapitulates the in vivo ICI-induced T cell recruitment and subsequent tumor regression, predicting the clinical results precisely. We demonstrated that circulating tumor-reactive T cells, which are effector memory-like with high expression levels of GNLY, CD44 and CD9, can serve as an indicator of the immunotherapy efficacy. Interestingly, enhanced inflammatory signaling in blood T cells is accompanied with prompted exhaustion and compromised anti-tumor function, when encountering with organoids. Our findings suggest that the GLI co-culture can be used for developing diagnostic strategies for precision immunotherapies as well as understanding the underlying mechanisms. Summary figure O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/597327v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@a0829dorg.highwire.dtl.DTLVardef@1df3083org.highwire.dtl.DTLVardef@1ea1065org.highwire.dtl.DTLVardef@1da9464_HPS_FORMAT_FIGEXP M_FIG C_FIG