🔬 Singapore's Pioneering Discovery in Tumor Immune Evasion

In a landmark achievement for oncology research, scientists from Singapore's National Cancer Centre Singapore (NCCS) and Duke-NUS Medical School have uncovered a critical mechanism by which tumors in head and neck squamous cell carcinoma evade the body's immune defenses. This breakthrough sheds light on how cancer cells communicate with immune cells to avoid destruction, offering fresh hope for more effective immunotherapies.

Head and neck squamous cell carcinoma, commonly abbreviated as HNSCC, represents a group of cancers originating in the squamous cells lining the mouth, throat, and sinuses. In Singapore, these cancers account for a significant portion of the over 800 annual head and neck cancer diagnoses, with metastasis to lymph nodes dramatically worsening patient outcomes. The study reveals that tumor cells exploit a protein called midkine to send a 'don't eat me' signal to exhausted CD8-positive T cells, the immune system's primary tumor killers.

This finding emerged from advanced single-cell RNA sequencing and CRISPR gene-editing screens, identifying 182 core genes involved in immune evasion. By targeting midkine alongside existing checkpoint inhibitors like anti-PD1 therapies, researchers demonstrated reactivation of dormant T cells, transforming the tumor microenvironment from immunosuppressive to hostile for cancer growth.

Unpacking Cancer Immune Evasion: The Basics

The human immune system constantly patrols for abnormal cells, using T cells to recognize and eliminate threats like tumors through antigen presentation on major histocompatibility complex class I (MHC-I) molecules. However, cancers evolve sophisticated strategies to dodge this surveillance, a process known as immune evasion.

One primary tactic is T cell exhaustion, where prolonged antigen exposure renders these cells dysfunctional, marked by high expression of inhibitory receptors like PD-1. Tumors further reinforce this by secreting factors that downregulate MHC-I or recruit regulatory T cells and myeloid-derived suppressor cells to create an immunosuppressive niche.

In HNSCC, the Singapore team's work highlights a novel intercellular signaling loop. Tumor cells upregulate midkine (MDK), a heparin-binding growth factor, which binds receptors on exhausted T cells. This interaction inhibits T cell activation and cytotoxicity, allowing metastatic subclones to seed lymph nodes undetected.

• Step 1: Primary tumor develops pre-metastatic cells with high MDK expression.
• Step 2: MDK engages receptors on CD8 T cells, emitting a survival signal.
• Step 3: Exhausted T cells fail to proliferate or release perforin/granzymes.
• Step 4: Cancer spreads, evading clearance.

Blocking MDK reverses this, synergizing with PD-1 blockade to restore T cell function, as shown in patient-derived models.

The Groundbreaking Study: Methods and Key Results

Led by Professor Gopal Iyer, Head of Head and Neck Surgery at Singapore General Hospital and NCCS, the multidisciplinary team—including experts from Duke-NUS Medical School, A*STAR's Singapore Immunology Network, and international collaborators—analyzed primary HNSCC tumors and matched lymph node metastases using single-cell transcriptomics.

They performed a genome-wide CRISPR knockout screen on tumor cells co-cultured with patient-derived T cells, pinpointing MDK as a top mediator. Functional validation in mouse models and organoids confirmed that MDK knockout enhanced T cell infiltration and tumor killing, while MDK overexpression promoted escape.

In human samples, high MDK correlated with poor prognosis and T cell exhaustion signatures. Combining MDK inhibition with immunotherapy not only halted metastasis but also elicited durable responses, suggesting a path to overcome resistance plaguing current treatments.

For more on the study, visit the NCCS announcement.

Singapore's Higher Education Ecosystem Driving Cancer Innovation

Duke-NUS Medical School, a collaboration between Duke University and the National University of Singapore (NUS), exemplifies Singapore's commitment to translational research. As a graduate-level institution, Duke-NUS trains clinician-scientists who bridge lab discoveries to bedside applications, with its Cancer and Stem Cell Biology Programme at the forefront of immunotherapy research.

NCCS, affiliated with Duke-NUS and Singapore General Hospital, hosts world-class facilities for HNSCC studies, supported by the National Research Foundation's investments. Complementary efforts at NUS's Cancer Science Institute (CSI) explore tumor microenvironments, while Nanyang Technological University (NTU)'s Lee Kong Chian School of Medicine advances AI-driven immune profiling.

A*STAR's SIgN provides immunological expertise, fostering interdisciplinary PhD programs that equip the next generation of researchers. These institutions collaborate via platforms like the Singapore Alliance for Research and Innovation, accelerating breakthroughs like the MDK discovery.

HNSCC Burden in Singapore: Stats and Challenges

Singapore faces a rising cancer tide, with 91,574 cases from 2019-2023 per the Singapore Cancer Registry. Despite declining mortality (down 21% since 2012 due to early detection and therapies), incidence climbs, with HNSCC contributing over 800 cases yearly—often linked to smoking, alcohol, and HPV.

Metastatic HNSCC has a dismal 40-50% five-year survival, underscoring the need for novel targets like MDK. Singapore's aging population amplifies risks, with one in four residents facing lifetime cancer odds.

Check latest stats at the NCCS Cancer Statistics page.

Therapeutic Horizons: From MDK to Clinical Reality

The MDK pathway opens doors to combination therapies. Preclinical data show MDK blockers restore 'eat me' signals, boosting PD-1 efficacy. Singapore's robust clinical trial infrastructure—over 1,000 active studies—positions it for swift translation.

Ongoing HNSCC trials at NCCS test PD-1 plus chemotherapy, with MDK as a potential biomarker. Broader immunotherapy advances, like CAR-T from NUHS, complement this.

• Benefits: Enhanced T cell persistence, reduced resistance.
• Risks: Cytokine storms, managed via monitoring.
• Comparisons: Superior to monotherapy in evasion-heavy tumors.

Personalized approaches via Duke-NUS genomics promise tailored regimens.

Singapore Universities: Hubs for Oncology Talent

Singapore's universities offer cutting-edge PhD and postdoc programs in cancer immunology. Duke-NUS's Integrated Biology and Medicine PhD emphasizes immune-oncology, while NUS CSI recruits for tumor evasion projects.

NTU's immunology labs explore T cell engineering, and A*STAR SIgN hosts fellowships. With competitive stipends (SGD 3,000+/month for PhDs), these programs attract global talent, fostering innovations like MDK targeting.

Stakeholder Perspectives: From Labs to Clinics

Prof Iyer emphasizes: 'Preserving T cells in metastatic sites allows reactivation, revolutionizing treatment.' Oncologists at NCCS note improved outcomes needed for late-stage HNSCC.

Patients advocate for accessible trials, while policymakers via NRF boost funding (SGD 25B for RIE2025). Balanced views highlight ethical AI use in profiling evasion genes.

Future Outlook: Curing Metastatic Cancers

By 2030, Singapore aims for top global cancer survival via Research, Innovation and Enterprise 2025. MDK-inspired drugs could enter trials by 2028, integrated with NGS for precision.

Challenges: Biomarker validation, combo toxicities. Solutions: Multi-omics at Duke-NUS, international trials. Actionable insights: Early HPV screening, quit smoking programs.

Singapore's model—unified funding, elite unis—positions it as Asia's oncology leader.

Photo by National Cancer Institute on Unsplash

Careers in Cancer Research: Join Singapore's Fight

Thriving opportunities abound: Postdocs at CSI (SGD 5,500+/month), faculty at Duke-NUS, research assistants at NCCS. Programs emphasize immunology, with PhDs leading to biotech roles (avg salary SGD 80K).

Explore Straits Times coverage for context.