Scientists from the Princeton branch of the Ludwig Institute for Cancer Research have revealed novel mechanisms through which a molecule derived from vitamin A disrupts the immune system’s capacity to combat cancer. This molecule, identified as all-trans retinoic acid, diminishes natural immune reactions against tumors and, in specific scenarios, hampers the efficacy of an innovative cancer vaccine approach.
Metabolites of vitamin A, referred to as retinoids, have historically generated considerable discussion due to their dual roles in promoting health and exacerbating diseases. The latest discoveries, outlined in two distinct scientific publications, shed light on this enduring debate. Moreover, these insights have spurred the invention of pioneering experimental medications aimed at blocking the cellular signaling route activated by retinoic acid.
How Retinoic Acid Compromises Cancer Vaccines
In one investigation, featured in Nature Immunology, Ludwig Princeton investigator Yibin Kang and doctoral candidate Cao Fang spearheaded the effort. Their work demonstrated that retinoic acid generated by dendritic cells (DCs)—crucial immune components that initiate defensive responses—can alter these cells to foster acceptance of tumors.
Such acceptance markedly diminishes the success rate of dendritic cell vaccines, an immunotherapy method intended to educate the immune system in identifying and eliminating cancer cells. The team further detailed the formulation and initial animal trials of a compound, KyA33, which prevents retinoic acid synthesis in both tumor cells and DCs. In these tests, KyA33 enhanced DC vaccine outcomes and exhibited promise as a standalone cancer treatment.
Innovative Methods to Interrupt Retinoid Pathways
A complementary study, directed by former Kang laboratory doctoral student Mark Esposito and appearing in iScience, concentrated on crafting inhibitors that halt retinoic acid generation and neutralize retinoid signaling entirely. Despite over a century of retinoid research, prior endeavors to develop secure drugs blocking their pathways have consistently fallen short.
The methodology in this paper integrated computational simulations with extensive drug screening processes. This combined tactic laid the groundwork for KyA33’s creation, signifying a breakthrough in addressing a signaling pathway that had long eluded pharmacological intervention.
Wide-Ranging Effects on Cancer Immunotherapy
‘Collectively, these results highlight the extensive role retinoic acid plays in dampening essential immune reactions against cancer,’ stated Kang. ‘Through our examination of this issue, we resolved a persistent pharmacological hurdle by inventing safe, targeted inhibitors of retinoic acid signaling and providing preclinical evidence for their application in cancer immunotherapy.’
The Dangerous Mechanism of Immune Suppression
An enzyme named ALDH1a3, frequently elevated in human cancer cells, generates retinoic acid. A similar enzyme, ALDH1a2, produces it in particular dendritic cell populations.
Upon production, retinoic acid binds to a receptor in the cell nucleus, initiating a cascade that modifies gene expression. In the intestinal tract, this mechanism supports the development of regulatory T cells (Tregs), which avert damaging autoimmune responses. Previously, the direct impact of retinoic acid on dendritic cells remained unclear.
The Pivotal Role of Dendritic Cells in Battling Cancer
Dendritic cells are essential orchestrators of immune activities. They vigilantly scan the body for indicators of infections or malignancies. Upon detecting threats, they break down abnormal protein pieces and display them as antigens to T cells, prompting these killer cells to eradicate infected or malignant entities.
To produce dendritic cell vaccines, immature cells are extracted from a patient’s bloodstream, cultured in labs with tumor-derived antigens, and reinfused to provoke robust anti-cancer immunity.
Even with advances in antigen selection, these vaccines frequently underperform. Fang, Kang, and collaborators—including Esposito and Princeton Branch Director Joshua Rabinowitz—aimed to uncover the underlying reasons.
The Suppressive Effects During Vaccine Manufacturing
‘We found that during standard DC vaccine preparation, maturing dendritic cells start producing ALDH1a2, leading to elevated retinoic acid levels,’ explained Fang. ‘The ensuing nuclear pathway inhibits DC development, weakening their capacity to stimulate anti-tumor responses. This undiscovered process probably accounts for the disappointing results of DC vaccines and similar therapies observed in numerous clinical studies.’
The issue extends further: retinoic acid from DCs promotes macrophages with reduced anti-cancer capabilities. As these ineffective macrophages proliferate instead of effective DCs, DC vaccine potency declines even more.
Revitalizing Immunity via Novel Pharmacology
By inhibiting ALDH1a2 genetically or with KyA33, the scientists restored DC maturation and immune activation potential. In melanoma mouse models, DC vaccines produced with KyA33 elicited potent, specific immune assaults that postponed tumor onset and curbed advancement.
KyA33 alone, when given to mice, functioned as a solo immunotherapy, shrinking tumors by bolstering immune activity.
Resolving the Vitamin A and Cancer Enigma
Crafting inhibitors for ALDH1a2 and ALDH1a3 marks a monumental accomplishment. Among twelve fundamental nuclear receptor pathways, retinoic acid’s was the earliest identified yet the sole one resistant to drug targeting until now.
The iScience paper elaborates on the computational and lab strategies that triumphed over this obstacle. These tools at last unraveled the vitamin A-cancer contradiction.
Lab tests show retinoic acid halting cancer cell proliferation or inducing death, fueling notions of vitamin A’s protective effects. Contrarily, major trials indicate high vitamin A consumption heightens cancer (and heart disease) risks and mortality. Tumor overexpression of ALDH1A enzymes correlates with poorer prognoses in various cancers. Earlier separation of ALDH1A roles from retinoic acid output proved elusive.
Cancer’s Exploitation of Retinoic Acid
‘Our research unveils the root of this contradiction,’ noted Esposito. ‘We demonstrated ALDH1a3 upregulation in numerous cancers to produce retinoic acid, while cancer cells evade retinoid receptor responses, dodging anti-growth or differentiation impacts. This clarifies vitamin A’s conflicting influence on tumor progression.’
Primarily, retinoic acid alters the tumor’s immune surroundings, not the cancer cells directly. Within the tumor microenvironment, it quells immune efforts, including T cell attacks on malignancy.
Validation came from ALDH1a3 inhibitors triggering vigorous immune offensives against tumors in mice, underscoring their immunotherapy promise.
Pathways to Innovative Therapies for Cancer and More
‘With drugs that precisely and safely block retinoic acid nuclear signaling, we’re forging a fresh cancer treatment paradigm,’ affirmed Kang.
Esposito and Kang founded Kayothera, a biotech firm advancing these ALDH1A inhibitors to clinical stages for retinoic acid-linked conditions like cancer, diabetes, and heart disease.
