1 of 1

From Smoke to Signaling: Linking Tobacco Exposure to Tumor Immunogenicity in Black Patients with Non Small Cell Lung Cancer (NSCLC)

�

Hashim Aslam, B.S.¹ , Mohammad Muhsin Chisti, M.D^.2 , Said Hafez Khayyata, M.D.³

​

Introduction

Methods

Results

References

Acknowledgements

Conclusions

• Commercial tobacco use remains the leading cause of preventable death in the United States
• Despite national declines, Michigan continues to have one of the highest adult smoking rates (18.9%)
•  From 1985-2018, 142,000 Michigan residents were diagnosed with non-small cell lung cancer (NSCLC), highlighting the ongoing public health burden of tobacco exposure in the state
• Smoking induces distinct molecular alterations in lung tumors contributing to biologically and histologically distinct NSCLC subtypes
• Modern NSCLC management relies on immunologic and molecular biomarkers to guide therapy
• Programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) play central roles in predicting response to immune checkpoint inhibitors such as pembrolizumab
• Elevated TMB* is associated with increased neoantigen formation and enhanced tumor immunogenicity, particularly when PD-L1 expression is low or equivocal (Fig.1)
• High PD-L1** expression (≥50%) supports first-line pembrolizumab monotherapy, while intermediate expression (1–49%) may guide combination regimens (Fig.2)

�

• Understanding how smoking history influences biomarkers may refine treatment selection, improve prognostication, and reduce unnecessary toxicity.
• The relationship between smoking intensity + duration and immunotherapy-relevant biomarkers remains underexplored in Black patients with NSCLC, a population historically underrepresented in molecular oncology research.
• Exploration may support precision oncology, inform biomarker-guided treatment strategies, and guide the development of tailored smoking cessation interventions for lung cancer patients.

​

* TMB represents the total number of somatic mutations within a tumor genome. Higher TMB increases neoantigen formation, enhancing tumor immunogenicity and response to immune checkpoint inhibitors. TMB is particularly informative when PD-L1 expression is low or intermediate and serves as a complementary biomarker for immunotherapy selection.

​

** PD-L1 is an immune regulatory protein expressed on tumor and immune cells that suppresses T-cell activation through PD-1 signaling, enabling immune evasion. Immune checkpoint inhibitors (e.g., pembrolizumab) block this pathway and restore antitumor immunity. Higher PD-L1 expression is associated with improved response to PD-1/PD-L1–targeted therapies and guides treatment selection in NSCLC.

​

We hypothesize that greater smoking exposure is associated with higher tumor mutational burden and altered PD-L1 expression in Black patients with NSCLC, with increasing smoking intensity and duration correlating with more immunogenic tumor profiles.

​

Primary Aim

To evaluate the association between smoking status and tumor mutational burden (TMB) and PD-L1 expression in Black patients with NSCLC.��

Secondary Objectives

1). To assess the impact of smoking intensity (pack-years) and duration on molecular tumor characteristics

2). To explore how smoking-related biomarker profiles may inform immunotherapy selection and prognostication

3). To establish preliminary data for future prospective studies examining smoking-driven resistance mechanisms and therapeutic response

Retrospective cohort study of patients with NSCLC evaluated at Corewell Health Royal Oak Hospital. Clinical, pathologic, and molecular data were extracted from the EMR.

​

Patient inclusion:

• Self-identified as African American/Black
• Confirmed diagnosis of NSCLC by pathology and/or molecular testing
• Evaluated between June 2019 and June 2023�Had available smoking history and next-generation sequencing (NGS) results�

Variables collected:

• Demographics: date of birth, sex, race
• Smoking history: smoking status (current, former, never), packs per day (PPD), pack-years
• Tumor characteristics: histology, grade, stage, primary tumor location�Molecular markers: PD-L1 expression, tumor mutational burden (TMB; mutations/Mb), microsatellite instability (MSI %), and NGS mutation categories

�Demographic baseline:

• Sample size (n) = 33 (17 female, 16 male) 
• 6 current smokers, 24 former smokers, 3 never smokers (~10%) 
• Average pack years for smokers ~ 31 years 
• Most prevalent histology was adenocarcinoma (90%), followed by squamous cell carcinoma (6.1%)
• Most common locations were RUL (33.3%) and LUL (30.3%) 
• 50% of cases were Stage IV, followed by Stage IIIA; few Stage II 

Biomarker insights:

Tobacco-related tumors show high TMB without corresponding MSI elevation &

Variable PD-L1 expression highlights need for multimodal biomarker assessment

MSI alone may underestimate immunotherapy potential��

Clinical relevance:

- Smoking history may help contextualize TMB, especially when PD-L1 is low/intermediate

- May serve as a clinical surrogate for immunogenicity when genomic testing is delayed

- Aligns with CheckMate 227 and KEYNOTE-042, showing immunotherapy benefit with high TMB despite modest PD-L1��

Equity & future directions:

Highlights need to expand molecular testing access in underserved populations

Supports investigation of serial genomic profiling and dynamic biomarkers in advanced NSCLC��

Limitations of incomplete molecular data availability for all patients and a geographically restricted sample group

I would like to acknowledge Dr. Mohammad Muhsin Chisti M.D, Dr. Said Hafez Khayyata M.D, Dr. Nitya Batra MBBS, Corewell Department of Pathology and Laboratory Medicine & the Embark Directors at OUWB for their invaluable guidance and support in the completion of this project.

​

No funding sources to disclose.

Figure 1: High TMB association with greater T-cell recognition via neoantigens

Figure 2: PD-L1 and T-cell tumor interactions

​

• Stage IV NSCLC patients demonstrated a significant positive association between smoking exposure and TMB (Spearman ρ = 0.58, p = 0.02)
• This relationship was not observed in Stage I–III disease or in the overall cohort

​

• No significant association between pack-years and PD-L1 expression
• Across all stages, sexes, and smoking categories

Both correlation and linear regression analyses were non-significant�

• Inverse relationship between pack-years and MSI
• Higher smoking exposure correlated with lower MSI percentages
• Strongest effect observed in male patients

Figure 3: TMB vs. Pack Years by Stage

Figure 4: TMB vs. Pack Years (Stage 4)

Figure 5: PD-1 vs. Pack Years by Stage

Figure 6: PDL-1 vs Pack Years by Sex

Figure 7: MSI vs. Pack Years by Stage

Figure 8: MSI vs. Pack Years by Sex

Table 1: Relationship Between TMB and Pack Years

�

​

- Saez de Gordoa K, Lopez I, Marginet M, et al. PD-L1 Expression in Non-Small Cell Lung Cancer: Data from a Referral Center in Spain. Diagnostics (Basel). 2021;11(8):1452. Published 2021 Aug 11. doi:10.3390/diagnostics11081452

�- Shao MM, Xu YP, Zhang JJ, Mao M, Wang MC. Tumor mutational burden as a predictive biomarker for non-small cell lung cancer treated with immune checkpoint inhibitors of PD-1/PD-L1. Clin Transl Oncol. 2024;26(6):1446-1458. doi:10.1007/s12094-023-03370-8

​

- Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non-Small-Cell Lung Cancer. N Engl J Med. 2023;389(6):491-503. doi:10.1056/NEJMoa2302983

�

​

In summary, among Stage IV patients, there was a moderate positive monotonic association between TMB and smoking exposure (Spearman ρ = 0.58, p = 0.02). 

​

In linear regression, the estimated mean increase in TMB per 10 pack-years was 2.15 (95% CI: −3.3 to 7.6, p = 0.44). The discrepancy suggests that the relationship may be non-linear or influenced by a few extreme observations rather than a consistent linear increase across the full range of pack-years.

​

Interpretation:

TMB may increase with smoking intensity, driven by tumor evolution and genomic instability

Relationship may reflect threshold effects or outlier exposures

¹ Oakland University William Beaumont School of Medicine, ² Department of Hematology and Oncology, Corewell Health East William Beaumont University Hospital , ³ Department of Pulmonary and Thoracic Pathology, Corewell Health East William Beaumont University Hospital

�