Control of CD8 T-Cell Infiltration into Tumors by Vasculature and Microenvironment

Abstract

CD8 T-cells are a critical brake on the initial development of tumors. In established tumors, the presence of CD8 T-cells is correlated with a positive patient prognosis, although immunosuppressive mechanisms limit their effectiveness and they are rarely curative without manipulation. Cancer immunotherapies aim to shift the balance back to dominant anti-tumor immunity through antibody blockade of immunosuppressive signaling pathways, vaccination, and adoptive transfer of activated or engineered T-cells. These approaches have yielded striking responses in small subsets of patients with solid tumors, most notably those with melanoma. Importantly, the subset of patients who respond to vaccination or immunosuppression blockade therapies are those with CD8 T-cells present in the tumor prior to initiating therapy. While current adoptive cell therapy approaches can be dramatically effective, they require infusion of extremely large numbers of T-cells, but the number that actually infiltrate the tumor is very small. Thus, poor representation of CD8 T-cells in tumors is a fundamental hurdle to successful immunotherapy, over and above the well-established barrier of immunosuppression. In this review, we discuss the factors that determine whether immune cells are present in tumors, with a focus on the representation of cytotoxic CD8 T-cells. We emphasize the critically important role of tumor-associated vasculature as a gateway that enables the active infiltration of both effector and naïve CD8 T-cells that exert anti-tumor activity. We also discuss strategies to enhance the gateway function and extend the effectiveness of immunotherapies to a broader set of cancer patients.

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

“…These CXCR3-ligands constitute the major chemokine axis enabling tumor infiltrating lymphocyte (TIL) entry into tumors, 24 and have been associated with TIL infiltration in several tumor models. 25 Moreover, increased CCL2 can also trigger T-cell recruitment through the macrophage ability to engulf and present antigens using MHC molecules, especially in the presence of trastuzumab by boosting antibody-dependent cellular phagocytosis-mediated killing of cancer cells. 19 Subsequently, the IFN-γ produced by recruited stimulated lymphocytes, which has been described to be crucial for Th1 immunity and trastuzumab response, 26 would in turn induce CXCLs in tumor cells followed by improved T cell-trafficking and maintenance of immune-enriched TME.…”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…Moreover, VEGF also contributes to form an immunosuppressive environment through inhibiting CTL migration to the tumor site. 96 Previous studies have shown that angiogenesis inhibitors normalize the vessels inside the tumor for effective drug delivery and convert the tumor microenvironment from immunosuppressive to an active state. 97,98 However, antiangiogenic agents tend to suppress the tumor growth rather than eliminate tumor cells and single-agent treatment is not supposed to produce a durable antitumor response.…”

Differential Expression of Homing Receptor Ligands on Tumor-Associated Vasculature that Control CD8 Effector T-cell Entry

“…E-selectin expression, although higher than that of normal tissue, was not significantly influenced by adaptive immunity. Increased HR ligand expression is associated with increased T-cell representation in the tumor microenvironment and improved tumor control (41). Collectively these studies suggest that HR ligand expression on most tumors limits CD8 + effector T-cell entry, but can be enhanced by augmenting endogenous immunity, directly activating tumor vascular EC, or manipulating the immunosuppressive tumor microenvironment.…”