# Role of intratumoral high endothelial venules in tumor immunity

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $374,578

## Abstract

Project Summary
Immune checkpoint inhibition emerged as promising cancer treatment strategies. However, only a subset of
patients respond to these therapies at present. Significant clinical evidence indicates that abundant tumor
infiltration of effector T cells and B cells is a prerequisite for the success of the immune checkpoint inhibition
therapies. However, these lymphocytes are largely excluded from many patients' tumors, which makes the tumor
unresponsive to the immunotherapies. High endothelial venules (HEV) are specialized venules that serve as
gateways for naïve lymphocyte recruitment, and these blood vessels can develop ectopically in tumors. High
HEV density in tumors correlate with favorable clinical outcomes, suggesting that the promotion of intratumoral
HEV formation would offer a novel opportunity to improve immunotherapies. The small GTPase R-Ras balances
angiogenic sprouting and vessel maturation, and normalizes tumor blood vessels. Several lines of evidence
indicate the importance of R-Ras for the formation of intratumoral HEVs. We hypothesize that intratumoral HEVs
shape the tumor immune landscape through efficient recruitment of lymphocytes, thereby creating the
immunostimulatory microenvironment favorable for immune checkpoint inhibition therapies. We propose a critical
role of R-Ras in this process by facilitating HEV formation in tumors.
Using novel genetic models of loss- and gain-of-function of R-Ras in endothelial cells, Aim 1 will demonstrate
that R-Ras facilitates the formation of HEVs within the tumor vasculature and determine how these HEVs affect
the tumor infiltration of T cells, B cells, dendritic cells, and other immune cell types in immunogenic mouse
mammary tumor and melanoma. The influence of intratumoral HEVs on cytokine environment will also be
determined. The analyses will be conducted by immunofluorescence, ELISA, FACS, and RNAseq. Clinical
cancer specimens will be examined to corroborate the findings from the mouse studies. Aim 2 will functionally
characterize tumor HEVs and analyze intratumoral priming of HEV-recruited T cells to a specific antigen using
adoptive transfer of naïve OT-1 T cells to OVA-expressing tumors. Aim 3 will determine how intratumoral HEVs
impact the immune destruction of tumors and the responsiveness to PD-1/PD-L1 inhibition therapies.
As the gateways for T cell/B cell recruitment to tumors, intratumoral HEVs are potential new targets to reprogram
the tumor immune landscape and to improve patients' response to immune checkpoint inhibitors. The expected
outcome of this study will provide the proof-of-concept for such ideas.

## Key facts

- **NIH application ID:** 10444131
- **Project number:** 1R01CA251192-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Masanobu Komatsu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $374,578
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444131

## Citation

> US National Institutes of Health, RePORTER application 10444131, Role of intratumoral high endothelial venules in tumor immunity (1R01CA251192-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10444131. Licensed CC0.

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