Terobosan Sel Kekebalan Tubuh: Ilmuwan Menemukan Sekutu Tersembunyi dalam Melawan Kanker

Kemajuan terbaru dalam penelitian imunoterapi telah mengungkapkan peran penting sel kekebalan baru dalam memerangi kanker, yang mengarah pada strategi potensial untuk meningkatkan kemanjuran pengobatan dan mengatasi resistensi.

Evolusi Imunoterapi

Selama beberapa dekade terakhir, imunoterapi telah merevolusi pengobatan kanker, memberikan pilihan efektif untuk penyakit yang dulunya dianggap tidak dapat diobati, termasuk melanoma, kanker paru-paru, dan kanker kandung kemih. Apa yang awalnya merupakan penelitian eksperimental di laboratorium kini telah beralih ke penerapan klinis yang mengubah hidup, menawarkan harapan baru bagi pasien dengan kondisi yang sulit diobati.

Bagaimana Imunoterapi Bekerja

Imunoterapi bekerja dengan memanfaatkan sistem kekebalan tubuh untuk menargetkan dan menghancurkan sel kanker. Hal ini dicapai dengan meningkatkan aktivitas kekebalan tubuh secara luas atau dengan berfokus pada jalur spesifik yang membantu sistem kekebalan mengenali, menyerang, dan menghilangkan sel kanker.

Meskipun terdapat kemajuan yang signifikan, imunoterapi masih menghadapi tantangan besar. Hambatan utamanya adalah kemampuan kanker untuk menghindari sistem kekebalan dengan mengubah sel-selnya agar tidak terdeteksi dan menciptakan lingkungan yang menekan kekebalan di dalam tumor. Akibatnya, banyak pasien tidak memberikan respons terhadap pengobatan yang ada saat ini—misalnya, lebih dari 50% pasien yang didiagnosis menderita melanoma, jenis kanker kulit paling agresif, hanya merasakan manfaat yang terbatas atau bahkan tidak sama sekali.

Penelitian Lanjutan dalam Imunoterapi Kanker

Sebagian besar cara kanker menghindari respon imun masih belum diketahui, sebagian besar disebabkan oleh rangkaian peristiwa molekuler yang kompleks dalam interaksi antara kanker dan sel imun. Memahami nuansa proses ini akan menjadi kunci untuk mengembangkan terapi yang lebih efektif.

Dalam studi yang dipimpin oleh Anna Obenauf, Senior Group Leader di IMP, tim peneliti internasional mengintegrasikan alat-alat mutakhir, termasuk model tikus melanoma, sel tunggal[{” attribute=”” tabindex=”0″ role=”link”>RNA sequencing, and advanced functional genetics and imaging technologies, to push the boundaries of our understanding of the immune system’s role in fighting cancer.

The study, now published in the journal Nature, reveals an additional type of immune cell involved in stimulating the immune response against cancer, opening up possibilities for new strategies to boost immunotherapy and potentially expand its benefits to more patients.

Rethinking the Cancer Immunity Cycle

Researchers studying the body’s antitumor defenses often refer to the ‘cancer immunity cycle’—a series of steps through which immune cells recognize and eliminate cancer cells. At the core of this cycle are T cells, the immune system’s primary cancer-fighting cells. But T cells do not work alone; they rely on activation from other immune cells, particularly antigen-presenting cells (APCs) such as dendritic cells–the main T cell activators.

The process begins when cancer cells release protein fragments, or antigens, that are captured by APCs. These cells present the antigens to T cells, effectively ‘priming’ them to recognize cancer cells as targets. Once activated in the lymph nodes, T cells travel to the tumor site to destroy it, releasing new antigens that restart the cycle of immune activation.

“The cancer immunity cycle, as we understand it today, is actually incomplete—we’re missing the crucial step of T cell reactivation within the tumor microenvironment,” says Anais Elewaut, co-first author of the study and a student in the Vienna BioCenter PhD Program. “We discovered that when T cells reach the tumor, they still need additional activation from other immune cells to be fully effective.”

Novel Findings and Future Directions

To identify the missing components in this process, the scientists used powerful cell models to investigate the factors that make cancer susceptible to the most common immunotherapies.

Two melanoma cell line models derived from mice that respond differently to commonly used therapies were generated at the Obenauf lab: one that responds well to both immunotherapy and targeted therapy, which applies substances aimed at specific cancer cells; the other resistant to both these treatment types. “With this system, we could closely compare responsive to resistant tumors, helping us figure out the key factors that determine whether a treatment will succeed or fail.”

Monocytes: A New Player in Cancer Immunity

The team first analyzed the tumor environment in both models by profiling gene expression at the level of single cells, and then sorted and quantified immune cell types based on specific markers on their surface. “We were very interested when we noticed lots of monocytes in responsive tumors compared to resistant ones. Monocytes are a type of immune cell never reported to play a role in T cell stimulation,” explains Elewaut. For the longest time, researchers had been looking at dendritic cells as the main activators of T cells, overlooking the role of other immune cells. In contrast, the resistant model had few monocytes, but was filled with suppressive macrophages, which are known to inhibit immune responses.
 
“Monocytes were thought to play a limited role in cancer immunity,” explains Guillem Estivill, co-first author of the study and a student in the Vienna BioCenter PhD Program. “Now we show how the presence or absence of these specific immune cells can lead to very different treatment outcomes.” Whereas dendritic cells are critical for kickstarting the cancer immunity cycle in the lymph node, both dendritic cells and monocytes are needed to fully activate T cells in the tumor.

The scientists found that monocytes can directly ‘borrow’ parts of cancer cells, including antigens, and present them to T cells. This process, called ‘cross-dressing’, allows monocytes to reactivate T cells, which boosts their function in recognizing and attacking cancer cells.

Restoring Immune Balance Against Cancer

The study also shows how cancer cells evade immunity by making it harder for T cells to stay activated and perform effectively. Cancer cells increase production of the molecule prostaglandin E2, which blocks the action of both monocytes and dendritic cells. Simultaneously, cancer cells decrease the production of interferons—molecules that stimulate immune activity— thereby further weakening the immune system’s ability to fight the tumor. “We’ve seen that restoring the levels of these molecules brings T cells back to their cancer-killing action through the activation of monocytes,” explains Estivill.

Building on this discovery, one promising strategy will be to use COX inhibitors, such as aspirin—drugs that block the cyclooxygenase (COX) enzyme, which is responsible for producing molecules that cause inflammation such as prostaglandin E2. Additionally, stimulating interferon production could enhance the immune system’s ability to combat cancer. These approaches could be combined with existing immunotherapies, providing new tools against cancers that are currently resistant to treatment.

The findings make monocytes promising targets to boost immunotherapies, with insights that have the potential to benefit a wide range of patients affected by cancers with similar molecular pathways to melanoma. These include lung, pancreatic, and colorectal cancer.

Future Directions in Immunotherapy

Future research will focus on exploring how stimulating T cells with monocytes and other immune cells plays out in different forms of immunotherapy. This knowledge could reveal new ways to overcome resistance to immunotherapies. “Clinical trials combining COX inhibitors and immunotherapy are on the horizon. And we already identified strategies to enhance their effectiveness,” says Anna Obenauf. “Our goal is to deepen the mechanistic understanding of anti-tumor immunity. I hope this will help us overcome resistance in more patients, making cancer immunotherapy a viable option for a broader range of patients.”

Reference: “Cancer cells impair monocyte-mediated T cell stimulation to evade immunity” by Anais Elewaut, Guillem Estivill, Felix Bayerl, Leticia Castillon, Maria Novatchkova, Elisabeth Pottendorfer, Lisa Hoffmann-Haas, Martin Schönlein, Trung Viet Nguyen, Martin Lauss, Francesco Andreatta, Milica Vulin, Izabela Krecioch, Jonas Bayerl, Anna-Marie Pedde, Naomi Fabre, Felix Holstein, Shona M. Cronin, Sarah Rieser, Denarda Dangaj Laniti, David Barras, George Coukos, Camelia Quek, Xinyu Bai, Miquel Muñoz i Ordoño, Thomas Wiesner, Johannes Zuber, Göran Jönsson, Jan P. Böttcher, Sakari Vanharanta and Anna C. Obenauf, 27 November 2024, Nature.
DOI: 10.1038/s41586-024-08257-4