Chapter Eight - Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment
Section snippets
Prognostic Significance of Immune Cell Representation in Tumors
A role for the immune system in cancer regression was suggested in the late-nineteenth century by William Coley, who observed that spontaneous remission of tumors sometimes occurred in patients who contracted acute bacterial infections. He subsequently developed a mixture of bacterial toxins that he believed activated the immune system and reported they were effective and even curative for some patients (Coley, 1893). Still, his method was controversial, and with the advent of chemo- and
CD8 T-Cell Representation in Tumors as a Predictive Marker of Responsiveness to Therapy
The emergence of clinically evident cancers reveals that despite the presence and activity of CD8 T-cells, tumors can escape their control (Vesely et al., 2011). Numerous strategies to harness and/or enhance the antitumor properties of CD8 T-cells have been developed, and in recent years, have led to encouraging successes. Melanoma has historically been the most studied tumor for immunotherapies, in part, because it is also the most responsive to a wide spectrum of such therapies. However,
Determinants of CD8 T-Cell Representation in Tumors and Other Tissues
The overall representation of T-cells in tissues, including tumors, is determined by the balance of several fundamental processes: cells entering tissues from the blood vasculature, cells leaving through draining lymphatics, and cells proliferating and dying in situ. To accumulate in a tumor at a peripheral site, however, typically effector T-cells are first activated by specific antigen in the draining LN (see Fig. 1). Tumors that are poorly infiltrated by effector T-cells may be poorly
Tumors Develop HEV-Like Vasculature
Classically, naïve CD8 T-cells are thought to primarily recirculate through the blood and secondary lymphoid organs to scan antigen-presenting cells for their cognate antigen (Von Andrian & Mackay, 2000). This tissue selectivity is based upon interactions of L-selectin and CCR7 with peripheral node addressin (PNAd) and CCL19/CCL21, respectively, which are normally selectively expressed on the specialized high endothelial venules (HEV) found in LN but not the vessels of peripheral tissues (
Rationale for Modifying Tumor-Associated Vasculature
As we have reviewed, characteristics of the tumor vasculature determine whether or not tumors are permissive to the entry of both effector and naïve CD8 T-cells. Because the presence of CD8 T-cells in tumors is such a strong prognostic factor and predictor of responsiveness to immunotherapies, strategies that can alter the tumor vasculature to support the enhanced entry of T-cells hold the potential to extend the effectiveness of these immunotherapies to a much broader cross section of patients
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