S100A9 enhances tumor immune suppression and cancer cell survival in small cell lung cancer – Nature

Report on S100A9 as a Therapeutic Target in Small Cell Lung Cancer (SCLC) in Alignment with Sustainable Development Goal 3

Introduction: The Challenge of SCLC to Global Health Objectives

Small cell lung cancer (SCLC) represents a significant global health challenge due to its aggressive nature, poor prognosis, and limited therapeutic advancements over recent decades. This high mortality rate directly impedes progress toward Sustainable Development Goal 3 (SDG 3), which aims to ensure healthy lives and promote well-being for all. Specifically, SCLC is a major contributor to premature mortality from non-communicable diseases, a key metric addressed in SDG Target 3.4. This report details findings on the S100A9 protein as a critical driver of SCLC progression and evaluates its inhibition as a novel therapeutic strategy to improve patient outcomes and contribute to achieving global health targets.

Key Findings on S100A9’s Role in SCLC Pathogenesis

Clinical Significance and Prognostic Value

Analysis of SCLC patient samples and cell lines revealed the critical role of S100A9 in disease severity, providing a potential biomarker to improve patient care in line with SDG 3.

• Aberrant Expression: The S100A9 protein is highly expressed in SCLC patients and aggressive SCLC cell lines compared to normal controls or other lung cancer subtypes.
• Prognostic Indicator: Elevated S100A9 expression was found to inversely correlate with overall survival in SCLC patients. This identifies S100A9 as a significant prognostic marker, the understanding of which is vital for developing more effective health interventions.
• Metastatic Association: S100A9 expression was notably enriched in metastatic SCLC cell lines, linking the protein to the advanced disease stages that are a primary cause of mortality.

Molecular Mechanisms Driving SCLC Progression

The study elucidated the molecular pathways through which S100A9 promotes SCLC, offering targets for therapeutic development essential for advancing SDG 3.

1. Promotion of Cell Survival and Migration: S100A9 activates the Akt and GSK3α/β/Snail signaling pathways, which are crucial for enhancing the survival and migratory capabilities of cancer cells.
2. Inhibition of Autophagy: S100A9 was found to reduce tumor cell autophagy, a key process in programmed cell death, through the regulation of Melanoma-Associated Antigen A3 (MAGE-A3). This pro-survival mechanism contributes to therapeutic resistance.
3. Autocrine Signaling Loop: The effects of S100A9 are mediated through its binding to the RAGE receptor in an autocrine fashion, creating a self-sustaining loop that drives tumor progression.

Therapeutic Implications and Contribution to SDG 3

Efficacy of S100A9 Inhibition in Preclinical Models

Pharmacological inhibition of S100A9 using tasquinimod was evaluated as a therapeutic strategy to address the urgent need for effective SCLC treatments, directly supporting the objectives of SDG Target 3.4.

• Reduced Tumor Growth: Both genetic depletion of S100A9 and pharmacological inhibition with tasquinimod significantly reduced tumor growth and metastasis in multiple preclinical SCLC models, including patient-derived xenografts (PDX).
• Synergy with Chemotherapy: Tasquinimod treatment, when combined with the standard-of-care chemotherapy agent cisplatin, demonstrated a significantly enhanced anti-tumor response and improved overall survival in an immunocompetent mouse model. This combination therapy approach is a promising step toward reducing mortality from this non-communicable disease.

Modulation of the Tumor Microenvironment

Targeting S100A9 reshapes the tumor microenvironment (TME) from an immunosuppressive to an immune-active state, a critical advancement for improving cancer therapies and public health outcomes.

1. Reduction of Immunosuppressive Cells: Tasquinimod treatment, alone or with cisplatin, significantly decreased the recruitment of myeloid-derived suppressor cells (MDSCs), which are known to inhibit anti-tumor immune responses.
2. Enhancement of Anti-Tumor Immunity: Inhibition of S100A9 led to a significant increase in the infiltration of activated CD8+ (CD69-positive) T cells into the tumor. These cytotoxic T cells are essential for identifying and eliminating cancer cells.

Conclusion: A Pathway Toward Improved SCLC Outcomes and Meeting Global Health Goals

This research establishes S100A9 as a key factor in SCLC progression, immune evasion, and poor patient survival. The findings demonstrate that targeting S100A9 with tasquinimod, particularly in combination with chemotherapy, is a promising therapeutic strategy. By reducing tumor growth, preventing metastasis, and converting the TME to an anti-tumor state, this approach offers a tangible pathway to improve clinical outcomes for SCLC patients. This work directly contributes to the global effort to combat non-communicable diseases and aligns with the core mission of Sustainable Development Goal 3 to reduce premature mortality and ensure healthier lives for all.

Analysis of Sustainable Development Goals (SDGs) in the Article

1. Which SDGs are addressed or connected to the issues highlighted in the article?

The primary Sustainable Development Goal (SDG) addressed in the article is:

• SDG 3: Good Health and Well-being

  The article is entirely focused on a critical health issue: Small Cell Lung Cancer (SCLC), which it describes as a “highly aggressive form of lung cancer associated with a poor prognosis.” The research aims to understand the molecular mechanisms of the disease and to “develop effective therapies to improve the clinical outcomes for SCLC patients.” By investigating the S100A9 protein as a therapeutic target and testing the efficacy of the drug tasquinimod, the study directly contributes to the overarching goal of promoting health and well-being by combating a major non-communicable disease.

2. What specific targets under those SDGs can be identified based on the article’s content?

Based on the focus of the research, the following specific targets under SDG 3 are relevant:

• Target 3.4: Reduce premature mortality from non-communicable diseases

  This target aims to “reduce by one third premature mortality from non-communicable diseases through prevention and treatment.” SCLC is a non-communicable disease with “poor prognosis and low survival rates.” The study’s central theme is to find a better treatment to combat this. The research demonstrates that high levels of the S100A9 protein are “associated with poor overall survival in SCLC.” The investigation into tasquinimod as a treatment that “conferred a survival advantage in SCLC” and could “extend the overall survival of SCLC patients” is a direct effort to improve treatment and reduce premature mortality from this specific cancer.

• Target 3.b: Support research and development of medicines and vaccines

  This target calls for supporting “the research and development of… medicines for the… non-communicable diseases.” The entire article is a detailed account of a research study aimed at identifying a new molecular target (S100A9) and developing a “promising therapeutic strategy” involving the pharmacological inhibitor tasquinimod. The study uses various preclinical models, including “patient-derived xenograft (PDX) mouse models,” to evaluate the drug’s effects, embodying the research and development process that this target seeks to promote.

3. Are there any indicators mentioned or implied in the article that can be used to measure progress towards the identified targets?

Yes, the article mentions and uses several specific indicators to measure the impact of the disease and the effectiveness of the proposed treatment, which align with the identified targets.

1. Overall Survival Rate

   This is a direct indicator for measuring mortality (Target 3.4). The article explicitly states that “S100A9 expression inversely correlates with overall survival in SCLC patients” and uses “Kaplan–Meier survival curves” to demonstrate this. Furthermore, a key finding was that S100A9 inhibition “demonstrated a significant survival advantage,” directly measuring progress in extending life.

2. Tumor Growth, Volume, and Weight

   These are key indicators of treatment efficacy. The study measures progress by showing that S100A9 depletion or pharmacological inhibition “reduced tumor growth.” Specific measurements mentioned include “tumor volume was measured weekly” and “tumor weight was analyzed at the end of the study,” with results showing a “significant decrease in tumor growth.”

3. Rate of Metastasis

   Metastasis is a primary cause of mortality in cancer. The article uses this as an indicator, noting that S100A9 promotes metastasis and its inhibition using tasquinimod “reduced… metastasis in vivo.” Specifically, the study “observed reduced liver metastasis in tasquinimod-treated animals.”

4. Development of New Therapeutic Strategies

   The research itself serves as an indicator of progress toward Target 3.b. The successful identification of S100A9 as a target and the validation of “tasquinimod alone or in combination with chemotherapy” as a potential treatment represent a measurable step in the development of new medicines for SCLC.

4. Summary Table of SDGs, Targets, and Indicators

Source: nature.com