Tuskegee, NIH researchers develop potential way to reprogram immune cells to fight cancer, other diseases

February 12, 2020

Contact:Michael Tullier, APR, Tuskegee University Office of Communications, Public Relations and Marketing,mtullier@tuskegee.edu, 334.724.4553

Photo of research team
亚博国际在线塔斯基吉大学's research team includes (L to R) doctoral students
Ruksana Amin, Ahmad Bin Salam and Jason White;
Dr. Balasubramanyam Karanam, assistant professor, Department of
Biology; Dr. Jesse M. Jaynes, professor, College of Agriculture,
Environment and Nutrition Sciences; and Dr. Clayton Yates, professor,
Department of Biology and director, Tuskegee Center for Cancer Research

Immune therapy research by a team of Tuskegee University faculty scientists and doctoral students — in partnership with the National Institutes of Health — shows great promise in the ability to reprogram immune cells, kill cancer cells and halt tumor growth in several types of cancer.

These research findings are described in detail in the article, "Mannose receptor (CD206) activation in tumor-associated macrophages enhances adaptive and innate antitumor immune responses," which appears theFebruary 12 edition ofScience Translational Medicine.

Cancerous tumors evade detection and boost their own growth by co-opting the body’s immune defenses. The newly developed therapeutic approach relies on small proteins called host defense peptides — ancient parts of our immune system’s defenses used by organisms to fend off bacteria, viruses and other foreign invaders. Using a novel algorithm that detects structural similarities, researchers have discovered that small stretches of amino acids in some of these peptides remained unchanged, or minimally changed, across organisms over millions of years of evolution.

The Tuskegee team — led by Clayton Yates, Ph.D., director of the Center for Cancer Research, and Jesse M. Jaynes, Ph.D. of the College of Agriculture, Environment and Nutrition Sciences — along with researchers from the NIH’s National Cancer Institute (NCI) and National Center for Advancing Translational Sciences (NCATS) have also demonstrated that the approach has potential for treating other diseases in addition to cancer.

“Cancer essentially pits our body’s immune system — specifically, macrophages, that would normally surround and destroy harmful bacteria — against us by turning these white blood cells into a protective forcefield,” Yates explained. “We’ve been able to show that these macrophages can be reprogrammed to their original purpose — to fight harmful cancer cells instead of defending them.”

In recent years, advances in immunotherapy — which harness the body’s immune system to fight disease — have garnered headlines as a potentially powerful tool against cancer. But many cancers termed “immunologically cold cancers” don’t respond to immunotherapies, including drugs called checkpoint inhibitors. As a result, researchers continue to seek new and different forms of immunotherapy to combat these often-fatal diseases.

“The field of immunotherapy holds immense promise and has already changed the cancer treatment landscape in immeasurable ways,” said NIH NCATS director Christopher Austin, M.D. “These findings point to a potential new way to use the immune system against cancer and demonstrate the value of a wide-ranging collaborative effort, including pre-clinical studies essential to better understand the biological mechanisms at play.”

Uncovering an entry point to reprogram the immune system

Computer model of RP-182
Computer model of RP-182

Several years ago, Jaynes — a Tuskegee biochemist whose research on plants and their pathogens has spanned four decades — was studying host defense peptides and their roles in infectious diseases in humans. These peptides punch holes in the cell membranes of bacteria. Jaynes consistently saw patterns of small stretches of 10 to 20 amino acids in these peptides conserved across many species. To Jaynes, this likely meant they could have an important function beyond their direct cell-killing function.

Based on these observations, Jaynes and Yates suspected that certain host defense peptides could have immunomodulatory functions and affect tumor-associated macrophages, which in healthy tissues are a first line of defense against infection. Host defense peptides attract macrophages to sites of tissue injury — a process cancer also uses to usurp macrophages to aid their own escape from the body’s immune system and to facilitate their growth.

In collaboration with Udo Rudloff, M.D., Ph.D., a physician-scientist at the National Cancer Institute, and NCATS’ team leader Juan Marugan, Ph.D., the joint Tuskegee-NIH team uncovered the receptor of the peptide CD206 on the surface of macrophages that regulates this process.

“CD206很可能演变为不同的入侵生物如细菌和病毒在巨噬细胞的切入点,”杰恩斯说。 “The team created several synthetic peptides, — including RP-182, which were designed to bind more strongly to the specific active motifs of the CD206 receptor.”

科学家们发现,当RP-182结合到CD206,它会导致在所述接收器结构的改变。 This in turn activates several biological pathways and sends new chemical signals to reprogram a type of macrophage to begin killing — literally “eating” — cancer cells.

How the peptide acts, what it does

有两大类肿瘤相关巨噬细胞的,或噬细胞:M1和M2。 M1s devour bacteria, viruses and cancer cells, and cause inflammation. M2s promote tissue recovery from the inflammation. When M2s fail to work properly, chronic inflammation can result in diseases like fibrosis, which is an overexpression of collagen leading to a buildup of connective tissue.

研究人员发现,RP-182转换M2巨噬细胞进入M1种类型,即肿瘤细胞吞食由这些重编程M2巨噬细胞,并且在治疗的肿瘤有朝着更M1和更少的M2巨噬细胞的转变。 Rudloff noted that binding to and altering the CD206 receptor also activates an array of other immune cells that help fight against cancer.

“这些肽4亿年前存在,” Rudloff说。 “We’ve connected an evolutionary process to an immune mechanism from which we can make a cancer drug. Our results could have broader implications for developing new approaches to immunotherapy.”

鉴定CD206作为M2巨噬细胞目标的球队后,无论是NCI和塔斯基吉团队发现,在不同的肿瘤类型的动物模型中显着的成效。亚博国际在线 The immune system of tumors was shifted toward improved tumor recognition and better surveillance to keep tumors in check. When RP-182 was given with chemotherapy or immune checkpoint therapy in pancreatic cancer, RP-182 cooperated with these treatments — which generally show no, or only minimal, activity in this highly lethal disease. The results suggested the possibility of combining this type of therapy with other treatments, including other immunotherapies.

RP-182是胰腺肿瘤特别有效 - 包括从患者肿瘤手术切除过程中去除,这有高水平CD206的既定胰腺肿瘤。 Yates and his group tested RP-182 in animal models of different cancers, showing that it worked not only on pancreatic cancer, but other cancers such as colon, breast, prostate and melanoma.

Expanding drug applications beyond cancer

通过扩展合作伙伴关系,总部位于加州的亨利·洛佩斯,博士,执行副总裁生物技术公司Riptide Bioscience Inc.,测得的药物对非癌症啮齿动物模型中的效果,例如肺纤维化 - 致死条件经常由异常肺巨噬细胞存款胶原驱动。 The drug reduced lung fibrosis and improved several clinical parameters associated with this pathology, thereby demonstrating RP-182’s potential for treating other diseases beyond cancer.

虽然Rudloff同意,初步结果显示在各种免疫治疗,其专注于癌症治疗仍然是球队的集体努力的前列采用RP-182的承诺。

“我们已经与演化过程的免疫机制,从中我们可以使抗癌药物。 Our results could have broader implications for developing new approaches to immunotherapy,” he explained.

Rudloff总结道:“对于我们的病人,我们的首要任务是进一步开发这些新的候选药物,作为癌症治疗的一个,并把它搬进诊所。 That’s still a while away.”

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