Abstract
Despite the success of immune checkpoint blockade in cancer, the number of patients that benefit from this revolutionary treatment option remains low. Therefore, efforts are being undertaken to sensitize tumors for immune checkpoint blockade, which includes combining immune checkpoint blocking agents such as anti-PD-1 antibodies with standard of care treatments. Here we report that a combination of chemotherapy (doxorubicin) and immune checkpoint blockade (anti-PD-1 antibodies) induces superior tumor control compared to chemotherapy and immune checkpoint blockade alone in the murine autochthonous polyoma middle T oncogene-driven (PyMT) mammary tumor model. Using whole transcriptome analysis, we identified a set of genes that were upregulated specifically upon chemoimmunotherapy. This gene signature and, more specifically, a condensed four-gene signature predicted favorable survival of human mammary carcinoma patients in the METABRIC cohort. Moreover, PyMT tumors treated with chemoimmunotherapy contained higher levels of cytotoxic lymphocytes, particularly natural killer cells (NK cells). Gene set enrichment analysis and bead-based ELISA measurements revealed increased IL-27 production and signaling in PyMT tumors upon chemoimmunotherapy. Moreover, IL-27 signaling improved NK cell cytotoxicity against PyMT cells in vitro. Taken together, our data support recent clinical observations indicating a benefit of chemoimmunotherapy compared to monotherapy in breast cancer and suggest potential underlying mechanisms.
Highlights
The idea to engage the immune system in the fight against cancer was already proposed in the early twentieth century but was mainly disregarded [1]
We asked whether a combinatorial approach consisting of doxorubicin (DOX) chemotherapy and anti-programmed death 1 (PD-1) antibody administration has an enhanced efficacy in reducing tumor growth compared to anti-PD-1 monotherapy
While immune checkpoint blockade such as anti-PD-1 and antiPD-L1 treatment proved to be impressively effective across a wide range of cancer types [37,38,39] only a small fraction of breast cancer patients benefits from anti-PD-(L)1 monotherapy
Summary
The idea to engage the immune system in the fight against cancer was already proposed in the early twentieth century but was mainly disregarded [1]. Synergism Between Chemo and Immunotherapy molecules cytotoxic T lymphocyte–associated protein 4 (CTLA4) and programmed death 1 (PD-1), respectively [2, 3] The blockade of those inhibitory checkpoint receptors by neutralizing monoclonal antibodies is well-known as immune checkpoint blockade and is already broadly used in the clinic. In patients with metastatic breast cancer, single-drug anti-PD1 therapy has shown little efficacy, due to a lower mutational load and a lower abundance of tumor-infiltrating lymphocytes (TILs) [7]. Chemotherapy was shown to increase the immune infiltrate and inhibit immunosuppressive components in the tumor microenvironment, which in turn can improve immune checkpoint blockade. Taken together, these findings substantiate combinatorial chemoimmunotherapy as a reasonable approach to fight breast cancer. We analyzed the impact of combinatorial chemotherapy and immune checkpoint blockade in the PyMT mammary carcinoma mouse model [13], since previous studies using this model failed to show effectiveness of anti-PD-1 monotherapy [14, 15]
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