Visualizing the Mechanistic Basis of Checkpoint Blockade Therapy in Cancer
Vinidhra Mani1, Jasper N. Pruessmann1, Robert T. Manguso2, Hans W. Pope2, Sarah Weischer1, Edward Y. Kim1, W. Nicholas Haining2, Thorsten R. Mempel1
1Harvard Medical School & Massachusetts General Hospital, 2Dana Farber Cancer Institute
The recent clinical success of checkpoint blockade therapy in several types of human malignancy has put tumor immunotherapy at the leading edge in the development of new cancer treatments. However, the mechanisms by which the immune system controls tumors are still incompletely understood, and how checkpoint blockade elicits effective anti-tumor immunity remains unclear. Traditionally, the cytotoxic activity of CD8+ T cells on tumor cells has been viewed as critical for tumor control, but classic studies have demonstrated the equally essential role of STAT1 activation in tumor cells. T and NK cell-produced IFN???? are thought to be critical inducers of STAT1 activity. Recent studies in cancer patients indicate that responsiveness of tumors to IFN???? is directly related to the clinical success of checkpoint blockade. Moreover, while direct tumor-killing by CTL is an important mechanism for clearance of the tumor, dynamic studies of CTL in the tumor microenvironment demonstrate that this does not quantitatively explain the dynamics of tumor rejection, indicating that CTL-derived cytokines may play an integral role in mediating tumor rejection. However, due to the diverse roles that IFN???? plays in anti-tumor immunity, its functions in a setting of tumor rejection remain incompletely understood and the context in which IFN???? is produced and released by CTL in vivo to then subsequently target tumor cells remains unknown. We have developed a system to simultaneously monitor, in vivo and in real time, CTL behavior in tumor tissue, STAT1 activation in tumor cells, and tumor cell death. We are studying the interrelation of these processes and how they are altered upon checkpoint blockade therapy. We present the results of our ongoing efforts to map the spatiotemporal dynamics of IFN???? signaling in tumor tissue in the context of checkpoint blockade.
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