MITF and Melanoma: New clues from the tumor immune landscape

April 4, 2025 Author Summary 0

MITF and Melanoma: New clues from the tumor immune landscape

Introduction: Why Understanding Melanoma’s Immune Environment Matters

Melanoma is one of the most dangerous types of skin cancer. It develops from melanocytes, the cells responsible for producing pigment in the skin. Although early-stage melanoma can often be treated successfully, advanced cases remain challenging. Some tumors respond well to new immunotherapy treatments, while others don’t—and researchers are still trying to understand why.

One promising area of investigation is the tumor microenvironment—the mix of immune cells, blood vessels, and molecules surrounding the tumor. A key feature of this environment is the presence of tumor-infiltrating lymphocytes (TILs). These are immune cells, mostly lymphocytes, that enter the tumor area. Their presence and pattern of distribution have been linked to how aggressive a tumor is and how it responds to treatment.

Another important factor in melanoma is the MITF protein (microphthalmia-associated transcription factor). MITF plays a central role in how melanoma cells grow and behave. When MITF levels are high, melanoma cells tend to be more differentiated and grow rapidly. When MITF is low, tumors may become more invasive and resistant to treatment.

The study by Vučinić and colleagues explores the relationship between MITF expression and TIL patterns. Their findings may offer new insights into how the immune system interacts with melanoma—and how we might better predict treatment outcomes.

Study Focus: A Closer Look at Immune Patterns in Tumors

To better understand the immune landscape, the researchers analyzed 81 melanoma tissue samples from patients treated between 2017 and 2021. They used a refined system to classify TIL patterns, based on a widely used method known as the BRISK classification.

Instead of the traditional three groups (BRISK, NON-BRISK, and ABSENT), they introduced six detailed subcategories to better capture where and how immune cells appear in the tumor—whether they are within the tumor, at the edges, or sparsely scattered.

They then measured the level of MITF protein in tumor cells and checked for MITF gene amplification, which refers to extra copies of the MITF gene that might increase protein production.

Key Finding: Higher MITF Linked to Stronger Immune Infiltration

One of the main findings was that MITF protein expression was highest in tumors where immune cells had infiltrated the tumor directly—especially in the group called BRISK B. In this category, MITF levels were often over 50%.

In contrast, tumors with fewer or no immune cells near or within them (the NON-BRISK and ABSENT groups) had significantly lower MITF levels. This suggests that how immune cells are arranged around the tumor—not just how many are there—may influence tumor behavior.

The researchers note:

“MITF protein expression in tumor cells is almost always greater than 50% when TIL falls within the BRISK B category.”

B Cells Play a Role: CD20+ Lymphocytes and MITF

Another interesting discovery involved CD20+ B lymphocytes, a type of immune cell not as commonly studied in melanoma as T cells. In 22% of the tumors, these B cells were found around the tumor. In those cases, MITF expression was significantly higher than in tumors without B cells.

This could mean that B lymphocytes play a more active role in melanoma than previously thought, possibly influencing tumor cell behavior through their presence in the immune environment.

What About T Cells?

The researchers also examined CD8+ (cytotoxic) and CD4+ (helper) T cells, as well as Foxp3+ regulatory T cells. While CD8+ and CD4+ cells were commonly present in tumors, the study did not find a clear link between their levels and MITF expression.

This suggests that the relationship between MITF and the immune system is more complex than just the presence of T cells. Other immune components or tumor-intrinsic factors may be influencing MITF behavior.

One exception was found in a specific melanoma type—lentigo maligna melanoma—where CD4+ lymphocytes were more common.

MITF Gene Amplification: A Weak Influence on Protein Levels

About 29% of tumors had extra copies of the MITF gene, but this did not clearly translate to higher protein expression. While there was a trend toward increased MITF levels in these cases, it was not statistically significant.

This finding indicates that MITF protein expression in melanoma may be driven more by the surrounding tumor environment than by genetic changes alone.

Clinical Context: What Else Did MITF Correlate With?

Higher MITF expression was also found in:

  • Tumors with greater thickness (based on Breslow scale).

  • Tumors that had spread to sentinel lymph nodes.

  • Tumors in later clinical stages (III–IV).

These associations suggest that MITF may reflect disease progression, but more data would be needed to determine whether it could serve as a reliable prognostic marker.

Why This Matters: Toward More Personalized Melanoma Treatment

This study highlights the potential for combining immune pattern analysis with molecular markers like MITF to better understand how melanoma behaves—and perhaps predict how it will respond to treatment.

Traditional approaches often look only at T cell density or tumor stage. But this research suggests that where immune cells are located, and how tumor cells are functioning at the molecular level, may provide more accurate insights.

The study’s refined BRISK classification system and its focus on MITF could help guide future research—and potentially improve how melanoma patients are selected for immunotherapy.

Limitations and Next Steps

The study authors acknowledge several limitations:

  • The sample size was modest (81 tumors).

  • The study did not include survival data or long-term outcomes.

  • The new TIL classification system, while more detailed, may need further validation.

Still, the findings offer a foundation for deeper exploration of how the immune system and tumor cells interact—and how this knowledge might inform more targeted melanoma therapies in the future.

Conclusion

Melanoma remains a challenging cancer to treat, in part because of the complexity of its interactions with the immune system. This study by Vučinić and colleagues adds to our understanding by showing that MITF expression is closely linked to the pattern of immune cell infiltration, especially in tumors where immune cells penetrate the tumor tissue.

The presence of B lymphocytes and the specific location of TILs may offer additional layers of insight into tumor biology. These findings could eventually contribute to more personalized treatment strategies and help predict which patients are more likely to respond to immunotherapy.

As the field of cancer immunology advances, integrating immune patterns and molecular profiles like MITF could become essential in improving care for people with melanoma.

The translation of the preceding English text in Croatian:

 

Uvod: Zašto je važno razumjeti imunološko okruženje melanoma

Melanom je jedan od najopasnijih oblika raka kože. Razvija se iz melanocita, stanica odgovornih za proizvodnju pigmenta u koži. Iako se melanom u ranoj fazi često može uspješno liječiti, uznapredovali slučajevi i dalje predstavljaju izazov. Neki tumori dobro reagiraju na novu imunoterapiju, dok drugi ne — a istraživači još uvijek pokušavaju shvatiti zašto.

Jedno od obećavajućih područja istraživanja je tumorski mikrookoliš — mješavina imunoloških stanica, krvnih žila i molekula koje okružuju tumor. Ključna značajka ovog okruženja je prisutnost limfocita infiltriranih u tumor (TIL – engl. tumor-infiltrating lymphocytes). To su imunološke stanice, uglavnom limfociti, koji ulaze u područje tumora. Njihova prisutnost i raspored povezani su s agresivnošću tumora i odgovorom na liječenje.

Drugi važan čimbenik u melanomu je MITF protein (mikroftalmija-asocirani transkripcijski faktor). MITF ima središnju ulogu u rastu i ponašanju stanica melanoma. Kada su razine MITF-a visoke, stanice melanoma obično su više diferencirane i brzo rastu. Kada je MITF nizak, tumori mogu postati invazivniji i otporniji na liječenje.

Studija Vučinića i suradnika istražuje odnos između ekspresije MITF-a i obrazaca TIL-a. Njihova otkrića mogla bi pružiti nove uvide u to kako imunološki sustav djeluje u interakciji s melanomom — i kako bi se mogao bolje predvidjeti ishod liječenja.

Fokus istraživanja: Detaljan uvid u imunološke obrasce u tumorima

Kako bi bolje razumjeli imunološki krajolik, istraživači su analizirali 81 uzorak tkiva melanoma od pacijenata liječenih između 2017. i 2021. godine. Koristili su poboljšani sustav za klasifikaciju obrazaca TIL-a, temeljen na široko korištenoj BRISK klasifikaciji.

Umjesto tradicionalne podjele u tri skupine (BRISK, NON-BRISK i ABSENT), uveli su šest detaljnih podkategorija kako bi preciznije opisali gdje se i kako imunološke stanice pojavljuju u tumoru — unutar tumora, na rubovima ili rijetko raspršene.

Zatim su mjerili razinu MITF proteina u tumorskim stanicama i provjeravali prisutnost pojačanja MITF gena, što se odnosi na dodatne kopije MITF gena koje bi mogle povećati proizvodnju proteina.

Ključno otkriće: Više MITF-a povezano je s jačom imunološkom infiltracijom

Jedno od glavnih otkrića bilo je da je ekspresija MITF proteina bila najviša u tumorima gdje su imunološke stanice prodrle izravno u tumor — osobito u skupini nazvanoj BRISK B. U toj kategoriji, razina MITF-a često je bila iznad 50%.

Nasuprot tome, tumori s malo ili bez imunoloških stanica u svojoj blizini (NON-BRISK i ABSENT skupine) imali su značajno niže razine MITF-a. Ovo sugerira da raspored imunoloških stanica oko tumora — a ne samo njihov broj — može utjecati na ponašanje tumora.

Istraživači navode:

„Ekspresija MITF proteina u tumorskim stanicama gotovo je uvijek veća od 50% kada TIL pripada BRISK B kategoriji.“

Uloga B stanica: CD20+ limfociti i MITF

Još jedno zanimljivo otkriće odnosilo se na CD20+ B limfocite, vrstu imunoloških stanica koje se rjeđe proučavaju u melanomu u usporedbi s T stanicama. U 22% tumora, ove B stanice pronađene su oko tumora. U tim slučajevima, ekspresija MITF-a bila je znatno viša nego u tumorima bez B stanica.

To bi moglo značiti da B limfociti imaju aktivniju ulogu u melanomu nego što se ranije mislilo, potencijalno utječući na ponašanje stanica tumora kroz svoju prisutnost u imunološkom okruženju.

A što je s T stanicama?

Istraživači su također ispitali CD8+ (citotoksične) i CD4+ (pomoćne) T stanice, kao i Foxp3+ regulatorne T stanice. Iako su CD8+ i CD4+ stanice bile često prisutne u tumorima, studija nije pronašla jasnu povezanost između njihove razine i ekspresije MITF-a.

To sugerira da je odnos između MITF-a i imunološkog sustava složeniji od same prisutnosti T stanica. Druge imunološke komponente ili unutarnji čimbenici tumora možda utječu na ponašanje MITF-a.

Jedan izuzetak pronađen je u specifičnom tipu melanoma — lentigo maligna melanomu — gdje su CD4+ limfociti bili češći.

Pojačanje MITF gena: Slab utjecaj na razine proteina

Oko 29% tumora imalo je dodatne kopije MITF gena, ali to nije jasno dovelo do više razine MITF proteina. Iako se primijetio trend porasta MITF-a u tim slučajevima, on nije bio statistički značajan.

Ovo otkriće ukazuje na to da ekspresija MITF proteina u melanomu može biti više pod utjecajem mikrookoliša tumora nego samih genetskih promjena.

Klinički kontekst: S čim je još MITF povezan?

Viša ekspresija MITF-a također je pronađena u:

  • Tumorima veće debljine (prema Breslow skali).

  • Tumorima koji su se proširili na sentinel limfne čvorove.

  • Tumorima u kasnijim kliničkim stadijima (III–IV).

Ove povezanosti sugeriraju da MITF može odražavati napredovanje bolesti, no potrebni su dodatni podaci kako bi se utvrdilo može li poslužiti kao pouzdan prognostički marker.

Zašto je ovo važno: Prema personaliziranijem liječenju melanoma

Ova studija ističe potencijal kombiniranja analize imunoloških obrazaca s molekularnim markerima poput MITF-a kako bi se bolje razumjelo ponašanje melanoma — i možda predvidjelo kako će tumor odgovoriti na liječenje.

Tradicionalni pristupi često promatraju samo gustoću T stanica ili stadij tumora. No, ovo istraživanje sugerira da lokacija imunoloških stanica i molekularno funkcioniranje tumorskih stanica mogu pružiti točnije uvide.

Poboljšana BRISK klasifikacija korištena u studiji i fokus na MITF mogli bi usmjeriti buduća istraživanja — i potencijalno poboljšati odabir pacijenata za imunoterapiju.

Ograničenja i budući koraci

Autori studije navode nekoliko ograničenja:

  • Veličina uzorka bila je ograničena (81 tumor).

  • Studija nije uključivala podatke o preživljenju ili dugoročnim ishodima.

  • Nova klasifikacija TIL-a, iako detaljnija, možda će trebati dodatnu validaciju.

Ipak, nalazi predstavljaju temelj za dublje istraživanje interakcije između imunološkog sustava i tumorskih stanica — i kako to znanje može pomoći u razvoju ciljane terapije melanoma u budućnosti.

Zaključak

Melanom i dalje predstavlja izazovan oblik raka za liječenje, djelomično zbog složenih interakcija s imunološkim sustavom. Studija Vučinića i suradnika doprinosi razumijevanju pokazujući da je ekspresija MITF-a usko povezana s obrascem infiltracije imunoloških stanica, osobito u tumorima gdje te stanice prodiru u tumorsko tkivo.

Prisutnost B limfocita i specifična lokacija TIL-a mogu pružiti dodatne uvide u biologiju tumora. Ova otkrića mogla bi jednog dana doprinijeti razvoju personaliziranih strategija liječenja i pomoći u predviđanju koji će pacijenti vjerojatnije odgovoriti na imunoterapiju.

Kako imunologija raka napreduje, integracija imunoloških obrazaca i molekularnih profila poput MITF-a mogla bi postati ključna u poboljšanju skrbi za osobe s melanomom.

Reference:

Damir Vučinić, Matea Lekić, Gordana Žauhar, Gordana Zamolo

The impact of MITF expression on tumor-infiltrating lymphocytes in melanoma: Insights into immune microenvironment dynamics.

Biomol Biomed [Internet]. 2025 Feb. 18 [cited 2025 Apr. 3];

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12125

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