Synergy of radiotherapy and PD-1 blockade in Kras-mutant lung cancer
Grit S. Herter-Sprie, … , Alec C. Kimmelman, Kwok-Kin Wong
Grit S. Herter-Sprie, … , Alec C. Kimmelman, Kwok-Kin Wong
Published June 16, 2016
Citation Information: JCI Insight. 2016;1(9):e87415. https://doi.org/10.1172/jci.insight.87415.
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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 4

Phenotyping of tumor-associated immune cell populations in RT-refractory αPD-1–treated Kras-mutant murine NSCLC.

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Phenotyping of tumor-associated immune cell populations in RT-refractory...
(A) Schematic representation of treatment schedule. αPD-1 treatment was initiated once tumor recurrence was detected (11–15 weeks after RT). (B) Tumor volume kinetics of RT-relapsed tumors treated with αPD-1. Each line represents one mouse (n = 4). Arrows indicate the beginning of αPD-1 treatment. (C) Representative flow cytometry data (live/single/total CD45+ cells). Total numbers of tumor-infiltrating lymphoid cells and myeloid cells of RT-refractory or RT-refractory αPD-1–treated tumors. (D) Total number of tumor-associated Tregs at indicated time points. CD8+/Treg ratio was calculated from C and D. (E) Expression of inhibitory T cell markers on CD8+ and CD4+ T cells of RT-recurrent and RT-recurrent αPD-1–treated tumors. Representative data are shown conducted with 4 RT-relapsed and 4 RT-relapsed αPD-1–treated mice (C–E). Data are represented as mean ± SEM. P values were calculated using 2-tailed Student’s t test. **P < 0.01; *P < 0.05. d, days; w, weeks; RT, radiation therapy; PD-1, programmed cell death 1; TAM, tumor-associated macrophages; TAN, tumor-associated neutrophils; Lag3, lymphocyte-activation gene 3; Tim3, T cell immunoglobulin and mucin-domain containing-3; Ctla4, cytotoxic T-lymphocyte–associated protein 4.