Hurdles to Lymphocyte Trafficking in the Tumor Microenvironment: Implications for Effective Immunotherapy

Abstract

An important consideration in the development of T cell-based cancer immunotherapy is that effector T cells must efficiently traffic to the tumor microenvironment in order to control malignant progression. T cell trafficking to target tissues is orchestrated by dynamic interactions between circulating lymphocytes and endothelial cells lining blood vessels. It is informative, in this regard, to compare and contrast the molecular mechanisms governing lymphocyte extravasation at distinct vascular sites: (1) high endothelial venules (HEV) of secondary lymphoid organs, which are portals for efficient trafficking of naive and central memory T lymphocytes; (2) non-activated endothelium of normal tissues that mediate relatively low basal levels of trafficking but are rapidly transformed into HEV-like vessels in response to local inflammatory stimuli; and (3) vessels within the intratumoral region and the surrounding peritumoral areas. These vessels can be distinguished by differential expression of hallmark trafficking molecules that function as molecular beacons directing lymphocyte migration across vascular barriers. This article reviews evidence that recruitment of effector T cells to the intratumoral microenvironment is impeded by sub-threshold expression of trafficking molecules on tumor microvessels. Emerging data support the thesis that when considered from the perspective of extravasation, vessels embedded within the intratumoral microenvironment of established tumors do not exhibit stereotypical characteristics of a chronic inflammatory state. A major challenge will be to develop therapeutic approaches to improve trafficking of effector T lymphocytes to tumor sites without skewing the balance in favor of a chronic inflammatory milieu that facilitates tumor maintenance and progression.

Synergy of adoptive T-cell therapy and intratumoral suicide gene therapy is mediated by host NK cells

“…29 To our surprise, however, trafficking studies showed no differences in OT-1T cell recruitment or accumulation, when measured by absolute numbers in either PBS-or GCV-treated tumors. Levels of T-cell trafficking to tumors might be confounded by the fact that the number of T cells detected within tumors will be a balance between cell trafficking and cell death.…”

“…First, the pro-inflammatory environment at the tumor site induced by HSVtk killing might serve as a potent means to attract more of the adoptively transferred antigen-specific T cells to the tumor, compared to tumors with no ongoing cell killing. 29 Alternatively, or additionally, the activated T cells, which reach the site of antigen expression at the tumor may be more active in terms of expression of effector functions such as perforin-mediated target cell lysis and interferon-g (IFN-g) expression. 28 Second, we recently delivered retroviral vectors encoding HSVtk to disseminated B16ova metastases by adsorbing retroviral particles to the surface of activated OT-1T cells.…”

Spontaneous Mammary Tumors Differ Widely in Their Inherent Sensitivity to Adoptively Transferred T Cells

“…Angiogenic factors [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)] and immunosuppressive cytokines (transforming growth factor-h and IL-10) can mediate this effect by down-regulating endothelial adhesion molecules, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1; ref. 39). Tumors from conventional MMTV/neu transgenic mice reportedly express both bFGF and VEGF but not VCAM-1 (16), which may account for the poor infiltration of some tumors in our model.…”

IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells

“…See Supplemental Methods for additional details. Briefly, 10 5 tumor cells were injected into surgically implanted dorsal skin flap single-sided window chambers (Research Instruments Inc.) (20,37). 14-21 days later, calcein-labeled T cells (2-10 × 10 7 cells/mouse) were gradually injected via the tail vein of anesthetized mice (1 mg/ml xylazine and 10 mg/ml ketamine; 10 ml/kg, i.p.)…”