# Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $507,168

## Abstract

The presence of CD8 T cells (TCD8) in tumors is a positive prognostic indicator of patient survival, but
representation of TCD8 in many tumors is poor. While this could be a consequence of poor intratumoral
proliferation, it is also the case that only a very small fraction of adoptively transferred TCD8 or CAR-T enter
tumors. Our published and preliminary data indicates that homing receptor ligand (HRL) expression on tumor
vasculature is suboptimal and that entry of TCD8 into tumors can be enhanced by relief of immunosuppression.
Our work also suggests a positive feedback model in which intratumoral effector activity from newly entering
TCD8 is needed to maintain HRL expression and sustain entry of newly arising effectors. Work conducted by
others has suggested that pro-angiogenic factors such as VEGF may limit TCD8 infiltration by multiple
mechanisms, including disorganized vascular structure, interference with cytokine signaling in endothelial cells
to induce HRL upregulation, and suppression of intratumoral immunity. However, how these different aspects
of angiogenesis influence direct TCD8 effector entry into tumors remains to be determined. There is also still
little understanding of the roles that innate immune cells and intratumoral Ag play in augmenting entry of TCD8
effectors. This multi-PI R01 application is a collaboration between two investigators with complementary
expertise. The Engelhard lab has identified: subpopulations of TCD8 effectors based on homing receptor (HR)
expression pattern; the patterns of HRL expression on tumor vasculature; and the HR/HRL pairs that mediate
TCD8 effector migration into tumors. The Kelly lab has focused on developing tools and using engineering
approaches to study the role of the endothelium in disease. Using phage display technology, they identified
hornerin, a novel non-VEGF induced protein overexpressed on tumor vasculature. Hornerin knockdown leads
to vessel normalization and increased perfusion without loss of blood vessels. Hornerin may be an ideal
molecule to attenuate in order to promote vessel normalization without the confounding pleiotropic effects
observed when inhibiting VEGF. These two investigators will use these novel tools and expertise to understand
how the direct entry of TCD8 into tumors is regulated by intratumoral Ag, tumor vasculature, and tumor
microenvironment. Aim 1 will determine the impact of intratumoral immunoregulatory mechanisms on HRL
expression on tumor vasculature and on exogenous TCD8 effector trafficking. Aim 2 will determine the impact of
pro-angiogenic factors and tumor vessel normalization on HRL expression on tumor vasculature and on
exogenous TCD8 effector trafficking. Aim 3 will determine the role of innate immune cells and intratumoral Ag in
promoting TCD8 effector trafficking into tumors. Overall, this work will illuminate factors that limit the migration of
tumor-specific T cells into tumors after vaccination or adoptive transfer, and suggest approaches ...

## Key facts

- **NIH application ID:** 10401362
- **Project number:** 5R01CA233716-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** VICTOR H ENGELHARD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $507,168
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10401362

## Citation

> US National Institutes of Health, RePORTER application 10401362, Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors (5R01CA233716-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10401362. Licensed CC0.

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