New immunotherapeutic approaches in sarcoma

JNI Oncology Lectures

Speaker: Matt van de Rijn (Stanford University Medical Center)

Subject: Immunotherapeutic approaches in sarcoma

Location: Erasmus MC Rotterdam

Date: Wednesday, 24.06.2015, 11:00-12:00

Author: Edgar Schönfeld

Up to 90% of a tumor can actually consist of non-cancer cells. A study conducted in 2011 [1] created a predictive model for cancer survival, based on stromal and epithelial morphological features in histological sections. It turned out that the epithelial features were outperformed by the stromal features, of which one corresponds to stromal inflammation. This highlights the importance of the tumor micro-environment, especially of macrophages and lymphocytes, which are at the heart of cancer immunotherapy.
Immunotherapy of cancer usually works in the following way. First a tumor-specific antigen has to be introduced to the body, for instance as a vaccine. This can be any protein that is specifically present in the tumor cells of interest. The dentric cells of the immune system take up those antigens. Furthermore, the dentric cells need an exogenously supplied activation signal (maturation signal) in order to induce an immune response. In lymphoid organs, those dentric cells trigger the production of cancer specific T-cells, which will invade the tumor. Last but not least, immunosuppressive responses by the tumor must be overcome as well.
Normally we expect that the immune system fights cancer cells on its own. However, it does not work if a tumor cell is too similar to its normal counterpart or if it gained a tolerance to the immune response. The novel approaches that Matt van de Rijn presented focused on the interaction between macrophages and cancer cells. When it comes to macrophages, which digest cancer cells and present its antigens to initiate an immune response (just like dendric cells), we distinguish between good and bad ones. Bad macrophages basically do not eat tumor cells (immunosuppressive response).
This is where anti-CSF1 and anti-CD47 could come into action, two antibodies that Matt van de Rijn labeled promising. LMS (Leiomyosarcoma) cells secrete CSF1 which attracts macrophages. This is associated with increased vascularity and a poor outcome in LMS patients. Here a high macrophage count is associated with poor outcome, because these macrophages are ‘bad’ ones, as they are tolerating the cancer cells. Anti-CSF1 antibodies show great efficacy in PVNS, in which CSF1 is also highly expressed (Pigmented Villonodula Synovitis). It is also possible to turn bad macrophages into good ones. LMS cells express the transmembrane protein CD47, which is a “don’t eat me” signal for macrophages. Upon binding to an antibody, the cells are not protected against macrophages anymore. Anti-CD47 antibodies have demonstrated that they are able to significantly reduce tumor size in mice [2] and are thought to be used for many malignancies.
Cancer immunotherapy is said to have come of age by now [3], perhaps the next striking results are just around the corner.

immunotherapy
[1] “Systematic Analysis of Breast Cancer Morphology Uncovers Stromal Features Associated with Survival”, Beck et al., Science Translational Medicine 2011

[2] “Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma”, Edris et al., PNAS April 24, 2012
vol. 109 no. 17

[3] “Cancer immunotherapy comes of age”, Ira Mellman,George Coukos & Glenn Dranoff,Nature 480, 480–489 (22 December 2011) doi:10.1038/nature10673

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