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

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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 antitumor 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 infiltrates 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 antitumor activity. We also discuss strategies to enhance the gateway function and extend the effectiveness of immunotherapies to a broader set of cancer patients.

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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      Our RNASeq results showed that Icam1 increased in KD and KD αPD1 tumors (Fig. 5C), and Vcam1 increased in KD αPD1 tumors (Fig. 5D). Icam1 and Vcam1 are integrin ligands that regulate leukocyte-endothelial interaction and play an important role in the structure of the tumor vasculature and T-cell trafficking into tumor.11 12 Vcam1 binds to VLA4 integrin to initiate T-cell slow rolling, whereas Icam1 binds to LFA1 to mediate cell arrest [31]. To confirm their role in CD8+ cell infiltration, we blocked CD18 and CD49D, which are the binding integrin partners to Icam1 and Vcam1, respectively.

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