Cytoreduction surgery reduces systemic myeloid suppressor cell populations and restores intratumoral immunotherapy effectiveness

Abstract

BackgroundMultiple immunotherapy approaches have improved adaptive anti-tumor immune responses in patients with early stage disease; however, results have been less dramatic when treating patients with late stage disease. These blunted responses are likely due to a host of factors, including changes in the tumor microenvironment and systemic immunosuppressive features, which accompany advanced tumor states. We hypothesized that cytoreductive surgery could control these immunosuppressive networks and restore the potency of immunotherapy in advanced disease scenarios.MethodsTo test these hypotheses, two representative intratumoral immunotherapies (an adenoviral vector encoding a suicide gene, AdV-tk, or a type-I interferon, Ad.IFNα) were tested in murine models of lung cancer. Cytoreductive surgery was performed following treatment of advanced tumors. Mechanistic underpinnings were investigated using flow cytometry, in vivo leukocyte depletion methods and in vivo tumor neutralization assays.ResultsAdV-tk and Ad.IFNα were effective in treating early lung cancers, but had little anti-tumor effects in late stage cancers. Interestingly, in late stage scenarios, surgical cytoreduction unmasked the anti-tumor potency of both immunotherapeutic approaches. Immune mechanisms that explained restoration in anti-tumor immune responses included increased CD8 T-cell trafficking and reduced myeloid derived suppressor cell populations.ConclusionThis study demonstrates that surgical resection combined with immunotherapy may be a rational therapeutic option for patients with advanced stage cancer.

Natural killer T cell activation overcomes immunosuppression to enhance clearance of postsurgical breast cancer metastasis in mice

“…3B and C), but this population expanded with progressive tumor growth. Consistent with previous reports, [47][48][49] the CD11b C Gr-1 C population declined following tumor resection. However, the CD11b C Gr-1 C population later surged as metastatic lesions developed in the mice receiving no additional treatment (data not shown), mice treated with unloaded DCs, and a subset of mice that relapsed following NKT cell activation therapy (Fig.…”

Changes in the local tumor microenvironment in recurrent cancers may explain the failure of vaccines after surgery

“…Fresh TC1 cells were mixed with CD8 T cells in a ratio of three CD8 T cells to one TC1 tumor cell (as described in ref. 32). The resulting mixture (1.5 × 10 6 CD8 T cells to 0.5 × 10 6 TC1 tumor cells) was injected s.c. into the flanks of five naive C57BL/6 mice.…”

Cytoreductive Radical Prostatectomy in Patients with Prostate Cancer and Low Volume Skeletal Metastases: Results of a Feasibility and Case-Control Study

“…5e9 Although the pathogenetic mechanisms involved in the advantageous effects of cytoreductive surgery are not fully understood, resection of an organ with the continuous capability to metastasize, removal of tumor promoting growth factors and immunosuppressive cytokines produced by the primary might contribute to the beneficial effects of cytoreductive surgery. 10,11 RP is usually ignored in the clinical scenario of metastatic PCA due to the common view that the biology of the disease is attributed to the metastatic spread and that it cannot be positively influenced by local treatment of the primary. Only recently has the potential benefit of CRP vs ADT alone in mPCA been hypothesized.…”