In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors
Danny N. Khalil, … , Jedd D. Wolchok, Taha Merghoub
Danny N. Khalil, … , Jedd D. Wolchok, Taha Merghoub
Published July 22, 2019
Citation Information: J Clin Invest. 2019;129(8):3435-3447. https://doi.org/10.1172/JCI128562.
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In situ vaccination with defined factors overcomes T cell exhaustion in distant tumors

Abstract

Irreversible T cell exhaustion limits the efficacy of programmed cell death 1 (PD-1) blockade. We observed that dual CD40-TLR4 stimulation within a single tumor restored PD-1 sensitivity and that this regimen triggered a systemic tumor-specific CD8+ T cell response. This approach effectively treated established tumors in diverse syngeneic cancer models, and the systemic effect was dependent on the injected tumor, indicating that treated tumors were converted into necessary components of this therapy. Strikingly, this approach was associated with the absence of exhausted PD-1hi T cells in treated and distant tumors, while sparing the intervening draining lymph node and spleen. Furthermore, patients with transcription changes like those induced by this therapy experienced improved progression-free survival with anti–PD-1 treatment. Dual CD40-TLR4 activation within a single tumor is thus an approach for overcoming resistance to PD-1 blockade that is unique in its ability to cause the loss of exhausted T cells within tumors while sparing nonmalignant tissues.

Authors

Danny N. Khalil, Nathan Suek, Luis Felipe Campesato, Sadna Budhu, David Redmond, Robert M. Samstein, Chirag Krishna, Katherine S. Panageas, Marinela Capanu, Sean Houghton, Daniel Hirschhorn, Roberta Zappasodi, Rachel Giese, Billel Gasmi, Michael Schneider, Aditi Gupta, James J. Harding, John Alec Moral, Vinod P. Balachandran, Jedd D. Wolchok, Taha Merghoub

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Figure 5

CMP selectively eliminates PD-1hi T cells in tumors while sparing nontumor tissues.

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CMP selectively eliminates PD-1hi T cells in tumors while sparing nontum...
(A) Expression profiling of distant tumors in bilateral tumor–bearing mice after 1 week of CMP treatment (n = 4/group). Shown are transcriptional changes induced by PD-1 monotherapy or CMP therapy relative to isotype control. (B) Heatmap generated using unsupervised clustering based on annotated gene sets from the Molecular Signatures Database defined by genes upregulated in effector versus exhausted CD8+ T cells during chronic infection (FDR q value = 7.35 × 10–11). (C) Distant tumors from bilateral B16F10 tumor–bearing mice were assessed by flow cytometry to determine the fraction of PD-1hiEomeshi terminally exhausted CD8+ T cells (n = 5/group) 1 week after isotype and CMP treatment. (D) IFN-γ and granzyme B expression was quantified by flow cytometry in the distant tumors and spleens 1 week after isotype or CMP treatment (n = 5/group). (E) Changes in the PD-1hi fraction of CD8+ T cells over time (n = 4/group) in isotype- and CMP-treated animals. (F) CD8+ T cell expression of TIM3, LAG3, and 2B4 at distant tumors and spleens (n = 5/group). (G) PD-1hi fraction of CD8+ T cells in treated tumors, distant tumors, spleens, and DLNs in response to treatment with CMP and each constituent agent (n = 4/group). Representative contour plots of 2 experiments are shown for the distant tumor. *P ≤ 0.05, ** P ≤ 0.01, ***P ≤ 0.001, and ****P ≤ 0.0001, by unpaired, 2-tailed Student’s t test.