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Soluble Microenvironment Appears to Impact How Melanoma Cells Interact With Immune Cells


Inflammatory microenvironments appear to enhance melanoma cells’ ability to control T-cell responses.

Melanoma may benefit from an inflammatory soluble microenvironment, according to a new study that found such microenvironments can help the cancer control T-cell responses.

The authors of the new report say the findings could lead to new therapeutic pathways against melanoma. The study was published in Frontiers in Oncology.

Corresponding author Felipe Saldanha-Araujo, PhD, of the University of Brasilia in Brazil, and colleagues explained that melanoma is only able to succeed insofar as it is able to evade the body’s natural immune response. Tumor cells adopt a number of approaches in order to achieve this task, including controlling the function of T-cells and generating regulatory T-cells.

Although progress has been made toward better understanding immune escape mechanisms in melanoma, Saldanha-Araujo and colleagues said many patients still experience relapse after being treated with the most advanced therapies. Thus, they said, significant work remains to better learn how to trap tumor cells in such a way that they can no longer evade the host’s immune system.

The investigators wondered if the tumor microenvironment might be an important reason why some cancers are able to achieve immune escape. Their hypothesis was that an inflammatory environment would make it easier for tumors to control T-cell function through paracrine mechanisms.

To test their hypothesis, they evaluated the ability of a metastatic melanoma cell line (MeWo) to control T-cell function in the conditioned media of resting peripheral blood mononuclear cells (PBMCs) and immune-activated PMBCs.

The cell lines were expanded in RPMI medium, resting conditioned media and immune-activated conditioned media, and the resulting secretome following cell expansion was then tested for its immunomodulatory potential in phytohaemagglutinin-activated PBMCs.

Saldanha-Araujo and colleagues found the inflammatory conditioned media induced higher levels of interferon-γ and interleukin-10 and higher IDO and PD-L1 expression compared with the resting conditioned media. The inflammatory secretome (iSec) inhibited T-cell activation and proliferation, the investigators said.

“Interestingly, PBMCs treated with iSec presented a reduced expression of the regulators of Th1 and Th2 responses T-BET and GATA-3, as well as low expression of IFN-γ, and co-stimulatory molecules TIM-3 and LAG-3,” they added.

The investigators said it was notable that the immunomodulatory effect they described involves 2 checkpoint molecules—TIM-3 and LAG-3—that are currently being investigated as therapeutic targets.

The investigators conceded that that finding would need to be validated in further study, but they suggested that it could have implications for the development of future melanoma therapies.

“Nevertheless, it is possible that if TIM-3 and LAG-3 present a reduced expression in immune cells that were exposed to the secretome of melanoma cells subjected to inflammatory conditions, they might not be the most effective targets to be explored in the clinic,” Saldanha-Araujo and colleagues wrote.

What is already clear, according to the authors, is that the soluble microenvironment is a relevant area when considering the question of immune escape in cancers like melanoma.

“Clinically, our observations allow one to suggest that the paracrine signaling promoted by the melanoma may alter the phenotype and function of tumor-neighboring immune cells that do not interact with cancer cells directly, possibly influencing clinical and treatment outcomes,” they wrote.


Bogéa GMR, Silva-Carvalho AÉ, Filiú-Braga LDC, Neves FAR, Saldanha-Araujo F. The inflammatory status of soluble microenvironment influences the capacity of melanoma cells to control T-cell responses. Front Oncol. Published online March 28, 2022. doi:10.3389/fonc.2022.858425

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