Lymphatic vessels active, anatomical determinants of effective antitumor immunity
Editor’s note: This is the second in a series of articles that spotlight research efforts supported through Cancer Research Institute’s Lloyd J. Old STAR program. The program provides up to $1.25 million over a 5-year period to mid-career scientists who pursue high-risk, high-reward research in cancer immunotherapy.
By Amanda W. Lund, PhD
The prevailing model of lymphatic vessel involvement in cancer is that tumor cells use lymphatic vessels as passive escape routes.
The more lymphatic vessels, the more escape routes and — consequently — the higher the probability of lymph node metastasis, distant spread and death.
Lymphatic vessels, however, do not exist to provide paths for metastatic spread. Instead, they connect peripheral tissues with downstream draining lymph nodes to provide the canonical and necessary route for peripheral immune surveillance.
It, therefore, has been proposed by our group and others that we should consider the immunological implications of lymphatic vessel remodeling in the context of tumor progression and response to therapy.
An interest in nonhematopoietic regulators of host immune responses is particularly salient as we come up against the exciting successes — and limitations — of T cell-targeted immunotherapies, such as immune checkpoint blockade, chimeric antigen receptor T cells and vaccines.
The limitations in efficacy and off-target toxicities associated with T-cell therapy may be addressed by investigating overlapping, tissue-based mechanisms of T-cell control.
Lymphatic vessels — as the anatomical link between tumors and downstream immune responses — are critical to immune responses and deserve our attention when considering new strategies to augment and control antitumor T-cell responses.
Anatomy of immune responses
My laboratory is exploring the functional contribution of lymphatic vessel biology to peripheral tissue immune responses.
In particular, we focus on the dermal lymphatic vasculature and its active contribution to the generation, maintenance and resolution of antimelanoma immunity.
We have demonstrated that lymphatic vessels are the necessary and most efficient route for immune priming downstream of cutaneous challenge — either tumor or viral. This work may indicate that the fidelity of regional lymphatic transport may determine immune surveillance at sites of tumor development.
It is important to consider, however, that — in addition to the well-established role lymphatic vessels play in antigen delivery to and T-cell priming in lymph nodes — lymphatic vessels may continue to regulate the maintenance and resolution of peripheral tissue immune responses.
We demonstrated that melanoma-associated, dermal lymphatic vessels adapt to infiltrating cytotoxic T cells and activate compensatory mechanisms that suppress local T-cell accumulation. Their suppressive function was mediated in part by expression of the inhibitory ligand PD-L1, providing the first evidence that nonhematopoietic, nontumor cells present functional immune checkpoints in tumor microenvironments.
Importantly, decoupling lymphatic vessel function from local, cytotoxic T-cell responses allowed for more durable tumor control and improved survival in animal models.
Thus, lymphatic vessels directly participate in tissue-based mechanisms of immune resolution that are hijacked in melanoma to facilitate adaptive immune resistance and immune escape.
A more complete understanding of the mechanistic link between lymphatic vessels and T cell-based immune responses will be critical to identify new therapeutic opportunities for immunotherapy.
Based on our previous work, we propose that lymphatic vessels tune tissue-based immune responses through sequential mechanisms of leukocyte, fluid and protein clearance to coordinate both the rapid response to challenge and eventual return to immune homeostasis.
With critical support from the Lloyd J. Old STAR Award from Cancer Research Institute, my laboratory will take a deep dive into the cellular and molecular mechanisms that govern lymphatic vessel control over immune responses.
We will test the central hypothesis that lymphatic vessels are active and context-dependent determinants of antitumor immunity by bringing together mouse models, rigorous immunological tools and strategies to track leukocyte trafficking and lymphatic transport in vivo.
First, we are exploring the dynamics of T-cell trafficking into and out of tumor microenvironments in order to suggest new control points through which to augment intratumoral T-cell repertoires.
Our recent work demonstrates that T cells actively exit tumors via lymphatic vessels, a process that is likely regulated by context-dependent lymphatic expression of chemokines that influence migratory behavior in situ.
The observation that T cells exit from tumors leads us to the obvious question of how transit through lymphatic structures effects T-cell phenotype, persistence and subsequent function. We will track T cells as they exit tumors and interact with the lymphatic endothelium to determine their subsequent role in tissue surveillance and tumor control.
Finally, we will focus on lymphatic fluid transport.
Though lymphatic vessels constitutively drain fluid at steady state, we have demonstrated that peripheral lymphatic capillaries activate junctional remodeling to limit macromolecule and pathogen efflux out of tissue following acute, cutaneous viral infection.
We will explore mechanisms underlying this response to determine the extent to which lymphatic transport may be tuned to impact immune responses against developing tumors.
Funding basic science
By integrating a molecular understanding of leukocyte trafficking and fluid transport via lymphatic vessels, we hope to outline new therapeutic opportunities that will contribute to the optimization of existing and new immunotherapies from immune checkpoint blockade to vaccines and CAR T-cell therapy.
Earlier this year, I was one of five scientists selected by Cancer Research Institute to receive the Lloyd J. Old STAR Award, which provides $1.25 million to each grantee over 5 years.
The award offers the flexibility to challenge existing paradigms and focus on the high-risk work that stands to radically expand our working model of lymphatic vessel involvement in immunity and human cancers.
Investments in basic immunobiology will shift paradigms and lead to unpredictable but long-lasting effects on clinical care.
We are excited to use this critical funding to develop new mechanistic insights that ultimately support the long-term goal of leveraging lymphatic vessel biology to improve response to immunotherapy and risk stratification. These efforts will further tip the immunological balance in the favor of the patient.
For more information:
Amanda W. Lund, PhD, is associate professor in the department of cell, developmental and cancer biology, the department of molecular microbiology and immunology, and the department of dermatology at Oregon Health & Science University. She also is a member of Knight Cancer Institute. She can be reached at email@example.com.
Disclosure: Lund reports no relevant financial disclosures.