Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer
Grit S. Herter-Sprie, Shohei Koyama, Houari Korideck, Josephine Hai, Jiehui Deng, Yvonne Y. Li, Kevin A. Buczkowski, Aaron K. Grant, Soumya Ullas, Kevin Rhee, Jillian D. Cavanaugh, Neermala Poudel Neupane, Camilla L. Christensen, Jan M. Herter, G. Mike Makrigiorgos, F. Stephen Hodi, Gordon J. Freeman, Glenn Dranoff, Peter S. Hammerman, Alec C. Kimmelman, Kwok-Kin Wong
Grit S. Herter-Sprie, Shohei Koyama, Houari Korideck, Josephine Hai, Jiehui Deng, Yvonne Y. Li, Kevin A. Buczkowski, Aaron K. Grant, Soumya Ullas, Kevin Rhee, Jillian D. Cavanaugh, Neermala Poudel Neupane, Camilla L. Christensen, Jan M. Herter, G. Mike Makrigiorgos, F. Stephen Hodi, Gordon J. Freeman, Glenn Dranoff, Peter S. Hammerman, Alec C. Kimmelman, Kwok-Kin Wong
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Research Article Immunology Oncology

Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer

Abstract

Radiation therapy (RT), a critical modality in the treatment of lung cancer, induces direct tumor cell death and augments tumor-specific immunity. However, despite initial tumor control, most patients suffer from locoregional relapse and/or metastatic disease following RT. The use of immunotherapy in non–small-cell lung cancer (NSCLC) could potentially change this outcome by enhancing the effects of RT. Here, we report significant (up to 70% volume reduction of the target lesion) and durable (up to 12 weeks) tumor regressions in conditional Kras-driven genetically engineered mouse models (GEMMs) of NSCLC treated with radiotherapy and a programmed cell death 1 antibody (αPD-1). However, while αPD-1 therapy was beneficial when combined with RT in radiation-naive tumors, αPD-1 therapy had no antineoplastic efficacy in RT-relapsed tumors and further induced T cell inhibitory markers in this setting. Furthermore, there was differential efficacy of αPD-1 plus RT among Kras-driven GEMMs, with additional loss of the tumor suppressor serine/threonine kinase 11/liver kinase B1 (Stk11/Lkb1) resulting in no synergistic efficacy. Taken together, our data provide evidence for a close interaction among RT, T cells, and the PD-1/PD-L1 axis and underscore the rationale for clinical combinatorial therapy with immune modulators and radiotherapy.

Authors

Grit S. Herter-Sprie, Shohei Koyama, Houari Korideck, Josephine Hai, Jiehui Deng, Yvonne Y. Li, Kevin A. Buczkowski, Aaron K. Grant, Soumya Ullas, Kevin Rhee, Jillian D. Cavanaugh, Neermala Poudel Neupane, Camilla L. Christensen, Jan M. Herter, G. Mike Makrigiorgos, F. Stephen Hodi, Gordon J. Freeman, Glenn Dranoff, Peter S. Hammerman, Alec C. Kimmelman, Kwok-Kin Wong

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Figure 1

Blockade of the PD-1/PD-L1 axis potentiates the antitumor efficacy of RT in Kras-mutant murine NSCLC.

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Blockade of the PD-1/PD-L1 axis potentiates the antitumor efficacy of RT...
(A) Schematic representation of combinatorial treatment schedule. (B) Representative MRI images of a Kras-driven tumor (one row represents 4 mm of lung) treated with RT and PD-1 blockade at different time points (baseline, 4 weeks, and 12 weeks after treatment initiation). H, heart (circled in red); T, tumor (circled with a white dotted line). (C) Tumor volume kinetics after dual treatment with RT and αPD-1. Each line represents one mouse (n = 10). (D) Treatment response to RT, αPD-1, or a combination of both is depicted. Data from unirradiated and RT cohort were previously published (8). Numbers below time points indicate amount of mice evaluated per group. (D–F) Data are represented as mean ± SEM. P values were calculated using 1-way ANOVA with Tukey’s multiple comparisons test. **P < 0.01. °This control group had to be discontinued due to extensive tumor burden or death. As fewer than 3 RT-treated mice were alive at this time point, statistical analysis was omitted. (E) Kaplan-Meier survival analysis of study cohorts presented in D calculated from treatment initiation. (F) Kaplan-Meier progression-free survival analysis of study cohorts presented in D calculated from treatment initiation. (E and F) P values were calculated using log-rank test corrected for multiple comparisons. A P value of less than 0.0167 (Bonferroni-corrected threshold) was considered statistically significant. *P < 0.05. d, days; w, weeks; RT, radiation therapy; PD-L1, programmed death-ligand 1; PD-1, programmed cell death 1.