Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction
Kyle Vaccaro, … , Aaron N. Hata, Kipp Weiskopf
Kyle Vaccaro, … , Aaron N. Hata, Kipp Weiskopf
Published March 14, 2024
Citation Information: J Clin Invest. 2024;134(9):e169315. https://doi.org/10.1172/JCI169315.
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Research Article Oncology

Targeted therapies prime oncogene-driven lung cancers for macrophage-mediated destruction

Abstract

Macrophage immune checkpoint inhibitors, such as anti-CD47 antibodies, show promise in clinical trials for solid and hematologic malignancies. However, the best strategies to use these therapies remain unknown, and ongoing studies suggest they may be most effective when used in combination with other anticancer agents. Here, we developed an unbiased, high-throughput screening platform to identify drugs that render lung cancer cells more vulnerable to macrophage attack, and we found that therapeutic synergy exists between genotype-directed therapies and anti-CD47 antibodies. In validation studies, we found that the combination of genotype-directed therapies and CD47 blockade elicited robust phagocytosis and eliminated persister cells in vitro and maximized antitumor responses in vivo. Importantly, these findings broadly applied to lung cancers with various RTK/MAPK pathway alterations — including EGFR mutations, ALK fusions, or KRASG12C mutations. We observed downregulation of β2-microglobulin and CD73 as molecular mechanisms contributing to enhanced sensitivity to macrophage attack. Our findings demonstrate that dual inhibition of the RTK/MAPK pathway and the CD47/SIRPa axis is a promising immunotherapeutic strategy. Our study provides strong rationale for testing this therapeutic combination in patients with lung cancers bearing driver mutations.

Authors

Kyle Vaccaro, Juliet Allen, Troy W. Whitfield, Asaf Maoz, Sarah Reeves, José Velarde, Dian Yang, Anna Meglan, Juliano Ribeiro, Jasmine Blandin, Nicole Phan, George W. Bell, Aaron N. Hata, Kipp Weiskopf

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Figure 5

The combination of targeted therapy and CD47 blockade enhances antitumor responses in mouse tumor models.

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The combination of targeted therapy and CD47 blockade enhances antitumor...
(A) EGFR mutant NSCLC PC9 xenograft model using NSG mice. Tumors were grown to approximately 500 mm3 and then mice were treated with vehicle control, an anti-CD47 antibody (250 μg 3 times weekly), osimertinib (5 mg/kg 5 times weekly), or the combination of anti-CD47 and osimertinib. Data depict mean tumor volume ± SEM (left), growth curves from individual mice (middle), or change in tumor volume from baseline (right). Complete responses were observed in 4 of 10 mice (40%) in the combination cohort. Data represent n = 9–11 mice per cohort combined from 2 independent experiments. (B) EGFR mutant NSCLC xenograft model of MGH134-1 patient-derived cells engrafted into NSG mice and treated as in A. (C) ALK+ xenograft model of NCI-H3122 cells engrafted into NSG mice and treated with vehicle control, an anti-CD47 antibody (250 μg 3 times weekly), lorlatinib (6 mg/kg 5 times weekly), or the combination of anti-CD47 and lorlatinib. (D) KRASG12C mutant xenograft model of NCI-H358 cells engrafted into NSG mice and treated with vehicle control, an anti-CD47 antibody (250 μg 3 times weekly), sotorasib (100 mg/kg 5 times weekly), or the combination of anti-CD47 and sotorasib. (E) Syngeneic model of KRASG12C mutant lung cancer using wild-type 3LL ΔNRAS cells or a CD47-KO variant engrafted into C57BL/6 mice. The mice were treated with vehicle control or sotorasib (30 mg/kg 5 times weekly) starting day 7 after engraftment. Data represent mean ± SEM from n = 9–10 mice per cohort. *P < 0.05 by paired t test for the indicated comparisons. (B–D) Data represent change in tumor volume from baseline with mean ± SEM of n = 4 mice per cohort. (A–D) *P < 0.05, **P < 0.01, ***P < 0. 001 by unpaired t test for combination versus targeted therapy.