Figure 6 from KRAS Inhibitor–Induced Cancer Cell Death Enhances Sensitivity to Immune-Mediated Bystander Killing of Drug-Resistant Subclones

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Adaptive immunity is required for durable responses. A, Experimental design for B and C. KRAS G12C KPAR1.3 wild-type (WT) or Emv2-KO tumors were treated for 6 days with RMC-4998 (100 mg/kg; G12Ci) ± RMC-4550 (SHP2i) or anti–PD-1 (aPD-1). B, Fraction of Emv2-specific CD8+ T cells of all immune cells (CD45+). Each dot represents one individual tumor; mean ± SD; one-way ANOVA Kruskal–Wallis test comparing vehicle with each treatment (only significant comparisons). C, Comparison of activation marker expression between Emv2-specific vs. non-specific CD8+ T cells for CD69 (left) and CD107a (right). D–F, Mixed subcutaneous tumors (BFP KRAS G12C cells plus 0.04% Luc-eGFP KRAS G12D cells) implanted in Rag1−/− GH mice were treated for 2 weeks with RMC-4998 (G12Ci) and/or RMC-4550 (SHP2i). Graphs combine the replicate results of n = 2. Tumor volume over time of individual tumors (D). Bioluminescence scans indicating the relative abundance of KRAS G12D cells (E). Probability of survival, stratified by treatment group (F). G and H, Mixed subcutaneous tumors (BFP KRAS G12C cells plus 0.04% Luc-eGFP KRAS G12D cells) engrafted in immunocompetent GH mice were treated for 3 weeks with vehicle or RMC-4998 + RMC-4550 (G12Ci + SHP2i). Either B cells or CD8+ T cells were selectively depleted by administering anti-CD20 (a-CD20) or anti-CD8 (a-CD8) antibodies, respectively. Tumor growth over time for indicated treatment groups. Complete responders (CR) indicated (G). Probability of survival, stratified by treatment group (H). *, P < 0.05; ***, P < 0.001, ****, P < 0.0001.

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