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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Research Article Oncology

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 3

CMP stimulates tumor-specific CD8+ T cells.

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CMP stimulates tumor-specific CD8+ T cells. (A) B16F10 tumor–bearing mic...
(A) B16F10 tumor–bearing mice were treated for 1 week with CMP or isotype control. CD8+ T cells were purified from spleens and restimulated with irradiated ID8 or B16F10 stimulator cells. Shown are IFN-γ+ cytotoxic T lymphocytes (CTLs) in CMP and isotype samples for both tumor cell types (n = 3–5/group). (B) One week after tumor challenge, mice bearing B16F10 tumors were adoptively transferred with 2 × 106 CellTrace Violet–labeled (CTV-labeled) Pmel-1 CD8+ T cells purified from naive TCR-transgenic mice. A single treatment with CMP or isotype was administered on day 8, and LNs were harvested on day 11 to assess proliferation. Quantification of undiluted cells is shown in the CTV dilution histograms (n = 4–5/group), which are representative of 2 experiments. (C) CD8+ T cells were purified from distant tumors of animals treated for 1 week with CMP and used for an ex vivo collagen-fibrin gel–based killing assay. CD8+ T cells were coincubated with B16 tumor cells, and tumor cell numbers were assessed using a clonogenic assay to determine the proportion of B16 cells killed and the killing constant. (D) Tumor-bearing mice were sacrificed after 1 week of CMP treatment, and DLNs were stained with H2-Db MHC class I multimers bearing peptides from the melanoma differentiation antigen gp100. Quantification of endogenous gp100-specific CD8+ T cells relative to the total CD8+ T cell population is shown in representative plots (n = 3–5/group). **P ≤ 0.01 and ****P ≤ 0.0001, by unpaired, 2-tailed Student’s t test.