Lymph nodes
Lymph nodes are small, bean-shaped glands throughout the body. They are part of the lymph system, which carries fluid (lymph fluid), nutrients, and waste material between the body tissues and the bloodstream. [Getty Images]

Research by scientists at Massachusetts General Hospital (MGH) and Boston University School of Medicine may help to explain why cancer cells that spread to lymph nodes (LN) can resist attack by immune cells. Their studies found that an increased physical force—known as solid stress—in metastatic lymph nodes effectively disrupts the ability of immune system cells to infiltrate the lymph node tumors and fight the cancer cells. The team’s experiments in mice showed that relieving solid stress led to a 15-fold increase in the presence of lymphocytes in lymph-node metastases.

Additional laboratory studies also showed that the antihypertensive drug losartan can act to relieve some of the effects of solid stress and so allow increased numbers of lymphocytes to infiltrate metastatic lesions. “We know that lymph nodes are often the first place cancer spreads as it progresses, said Timothy P. Padera, PhD, an investigator in radiation oncology at MGH and a 2021–2026 MGH research scholar. “We also know that our immune system can attack and kill cancer cells. One of the perplexing questions that has been at the core of the recent work in my lab is how can organs that generate our immune responses—lymph nodes—permit cancer cells to survive and take them over instead of attacking them? This was the driving motivation behind this study.”

Padera is co-corresponding author of the team’s paper in Nature Biomedical Engineering, in which the team concluded, “Solid-stress-mediated impairment of lymphocyte infiltration into lymph-node metastases suggests a therapeutic route for overcoming T-cell exclusion during immunotherapy … Our data suggest that controlling solid stresses in LNs may enhance anticancer immunity by improving T-cell trafficking into LN metastases.” The paper is titled, “Solid stress impairs lymphocyte infiltration into lymph-node metastases.”

Lymph nodes are critical to the body’s immune response against tumors, but cancer cells that metastasize to lymph nodes can often avoid destruction by immune cells, the authors wrote. “Tumor-draining LNs (TDLNs) have recently been shown to be critical for the generation of antitumor T-cell responses and for the response to immunotherapy. Paradoxically, it is these organs, which should be generating antitumor immunity, that are frequently the first site of spread and growth of metastatic cancers.” Moreover, the team noted, scientists don’t really understand the mechanisms that allow cancer cells to evade immune surveillance in the lymph nodes.

Solid stresses are mechanical forces generated by the growth of cancer cells and the extracellular matrix, which can perturb tissue architecture, and effectively compress blood and lymphatic vessels in primary tumors. “We recently measured elevated solid stresses in metastatic LN, but their consequences in this immune organ are unknown,” the authors acknowledged. For their newly reported studies, Padera and colleagues carried out analyses of patient tissue from breast, colon, and head and neck cancers, and designed experiments using animal models of breast cancer lymph node metastases. Their results indicated that the immune system T cells are, in fact, abundant in metastatic lymph nodes, but fail to penetrate tumors that have spread to these nodes.

The team measured the increased physical forces—solid stress—in lymph nodes that contained metastatic lesions. “We hypothesized that solid stress in lymph node tumors can impair both blood flow and the T-cell trafficking capacity of blood vessels in lymph nodes,” said lead and co-corresponding author Dennis Jones, PhD, an assistant professor of pathology & laboratory medicine at the Boston University School of Medicine. They found that in tissue from patients with breast, colon, and head and neck cancers, as well as in mice with spontaneously developing breast-cancer lymph-node metastases, “ … lymphocyte exclusion from nodal lesions is associated with the presence of solid stress caused by lesion growth, that solid stress induces reductions in the number of functional high endothelial venules [HEVs] in the nodes.”

The scientists also developed a device to compress lymph nodes, so that they could simulate the gradual growth of lymph node metastases. When they applied compressive force to lymph nodes they found a clear link between the physical force and disruption of T-cell entry into lymph nodes. “Collectively, the compression apparatus reproduces several features of macrometastatic nodal lesions and these data indicate that compressive forces cause the collapse of LN vessels and the reduction of lymphocyte recruitment into LNs,” they wrote. Moreover, the scientists added, their newly reported experimental data suggest that reducing solid stress in tumor-involved LNs may “ … promote the normalization of HEVs in LN metastases to enable T-cell entry.”

Padera continued: “Our findings indicate that as cancer cells grow in the lymph node, they reorganize and alter the lymph node, disabling critical functional responses of the immune system … By understanding how cancer cells are disabling lymph node function, we hope to fight back to help the lymph nodes generate anticancer immune responses, which will help fight cancer cells everywhere in the body.”

The team also found that a blood pressure-reducing drug called losartan, acts to alleviate solid stress, which then boosted the numbers of blood vessels and T cells in lymph node metastases. These findings suggest that alleviating solid stress could be a potential strategy for improving T cell entry into tumors. “Losartan has previously been shown to reduce solid stress by reducing collagen in the tumor microenvironment,” the investigators explained. “Treatment of metastatic LNs with losartan after primary tumor removal resulted in reduced collagen within metastatic lesions and increased the presence of HEVs and lymphocytes within LN metastatic lesions. These data suggest that targeting solid stress using losartan can improve lymphocytic infiltration into LN tumors.”

Jones further noted, “Our work now leads to many important additional questions. Does losartan treatment combined with immunotherapy cause the eradication of metastatic cancer cells in lymph nodes by T-cell killing? And further, does this lead to a strong systemic anticancer immune response that helps clear the cancer from the entire body?” Jones suggests that finding the answers to these questions could lead to new treatment strategies for patients with metastatic cancer.

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