TTF-1 expression stratifies chemoimmunotherapy benefits in PD-L1-negative lung adenocarcinoma: a real-world biomarker validation

Introduction

Over the past decade, immune checkpoint inhibitors (ICIs) have demonstrated remarkable therapeutic efficacy in patients with advanced lung adenocarcinoma who lack driver gene alterations (1). For programmed death-ligand 1 (PD-L1)-positive (≥1%) tumors, particularly those with high PD-L1 expression (≥50%), the clinical benefits of immunotherapy—either as monotherapy or combined with chemotherapy—have been well established (2,3). However, PD-L1-negative (<1%) patients account for 35–40% of lung adenocarcinoma cases, and whether and to what extent this subgroup benefits from immunotherapy remains a critical unresolved issue in both research and clinical practice (4,5).

Current evidence on immunotherapy for PD-L1-negative advanced non-squamous non-small cell lung cancer (NSCLC) primarily derives from subgroup analyses of pivotal trials such as KEYNOTE-189 and IMpower-132 (6,7). Although these studies suggest modest survival improvements with chemoimmunotherapy in PD-L1-negative populations, the benefits are substantially inferior to those observed in PD-L1-positive cohorts. Given the prevalence of PD-L1-negative disease, there is an urgent need to identify predictive biomarkers for refining patient selection within this heterogeneous population.

Thyroid transcription factor-1 (TTF-1), also known as NKX2-1, is a homeodomain transcription factor essential for lung morphogenesis and epithelial differentiation (8). As a widely used immunohistochemical marker, TTF-1 is expressed in 70–80% of lung adenocarcinomas but rarely in squamous cell carcinomas (<10%) (9). Beyond its diagnostic utility, TTF-1 is a prognostic predictor in lung adenocarcinoma, with positive expression correlating with improved outcomes and demonstrating superior predictive value over tumor grade (10-12). Emerging evidence suggests that TTF-1 positivity may be associated with superior responses to immunotherapy alone, while TTF-1-negative tumors could derive greater benefits from chemoimmunotherapy (13-15). Notably, Nishioka et al. (16,17) demonstrated that the adverse prognostic impact of TTF-1 negativity in PD-L1-positive NSCLC patients might be mitigated by immunotherapy. These findings suggest TTF-1 as a potential predictive biomarker for stratifying immunotherapy-responsive populations.

However, no studies have specifically evaluated the role of TTF-1 expression in predicting response to immunotherapy for PD-L1-negative lung adenocarcinoma. To address this gap, we investigated the predictive value of TTF-1 in this population, with the goal of refining patient stratification and guiding personalized therapeutic strategies. We present this article in accordance with the REMARK reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-644/rc).

Methods

Study design and patients

We conducted a retrospective study of patients with advanced lung adenocarcinoma who received chemotherapy or chemoimmunotherapy at General Hospital of Southern Theater Command between January 2018 and January 2024. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of General Hospital of Southern Theater Command (approval No. NZLLKZ2024159), which waived the requirement for informed consent due to the anonymized use of clinical data. Inclusion criteria were: (I) histologically confirmed lung adenocarcinoma; (II) tumor node metastasis (TNM) stage III–IV [American Joint Committee on Cancer (AJCC) 8th edition (18)] or postoperative recurrence; (III) available TTF-1 expression results; (IV) PD-L1 tumor proportion score <1% (PD-L1-negative). Exclusion criteria included: (I) missing TTF-1 expression data; (II) presence of driver gene mutations; (III) non-platinum-based chemotherapy or regimens other than pemetrexed- or taxane-platinum combinations. Clinical data were extracted from electronic medical records. PD-L1 expression was assessed using the rabbit monoclonal 22C3 pharmDx antibody (clone 22C3; Dako North America, Inc., Carpinteria, CA, USA) via immunohistochemistry (IHC) on formalin-fixed paraffin-embedded tumor sections, with human placenta as positive controls. PD-L1 negativity was defined as tumor proportion score (TPS) <1%. TTF-1 expression was determined using the mouse monoclonal anti-TTF-1 antibody SPT24 (IHC) with each batch containing negative control slides (primary antibody omitted). TTF-1 positivity was defined as nuclear staining in ≥1% tumor cells. Both biomarkers were independently evaluated by two experienced pathologists blinded to clinical outcomes. Discordant cases were resolved through multi-head microscope review.

Treatment and outcomes

We compared first-line chemoimmunotherapy versus chemotherapy in PD-L1-negative advanced lung adenocarcinoma, stratified by TTF-1 expression. Chemotherapy regimens consisted of platinum-based schemes combined with pemetrexed or taxanes (such as paclitaxel injection, liposomal paclitaxel, docetaxel injection, and albumin-bound paclitaxel), with carboplatin or cisplatin as the platinum drugs. Immunotherapy agents were all PD-1 monoclonal antibodies, including pembrolizumab, camrelizumab, and sintilimab, etc. Progression-free survival (PFS) was defined as the time from treatment initiation to disease progression or death. Overall survival (OS) was measured from treatment initiation to death from any cause. The follow-up cutoff date was February 1, 2025, and the median follow-up duration was 19.8 months.

Statistical analysis

Baseline characteristics were compared using Mann-Whitney U tests for continuous variables and Fisher’s exact tests for categorical variables. Survival curves were generated using the Kaplan-Meier method and compared via log-rank tests. Multivariable Cox proportional hazards models evaluated associations between patient characteristics and survival outcomes, with age, Eastern Cooperative Oncology Group performance status (ECOG-PS) score, and liver metastasis included as covariates selected based on standardized mean differences (SMDs >0.1) and clinical relevance; results were reported as adjusted hazard ratio (aHR) with 95% confidence intervals (CIs). All tests were two-sided, with P<0.05 considered statistically significant. Analyses were performed using GraphPad Prism 8.0 (GraphPad Software, La Jolla, CA, USA) and SPSS 25.0 (IBM Corp., Armonk, NY, USA).

Results

Patient characteristics

Among 412 consecutive PD-L1-negative advanced lung adenocarcinoma patients who received first-line chemotherapy or chemoimmunotherapy between January 2018 and January 2024, 72 were excluded due to missing TTF-1 expression, 38 for harboring driver gene mutations, and 49 for non-platinum-based or non-pemetrexed/taxane-platinum regimens. Ultimately, 253 patients were enrolled (Figure 1). The baseline characteristics between the chemotherapy group and the chemoimmunotherapy group demonstrated acceptable baseline balance within both the TTF-1-positive cohort (n=187) and the TTF-1-negative cohort (n=66), as summarized in Table 1.

Figure 1 Patient enrollment flowchart. PD-L1, programmed death-ligand 1; TTF-1, thyroid transcription factor-1.

Chemoimmunotherapy vs. chemotherapy stratified by TTF-1 expression

In the overall cohort of 253 patients, chemoimmunotherapy improved median PFS [7.9 vs. 6.6 months, hazard ratio (HR) =0.74, P=0.03] and OS (17.5 vs. 15.4 months, HR =0.69, P=0.02) over chemotherapy (Figure 2A,2B). Stratified by TTF-1 status, TTF-1-negative patients (n=66) receiving chemoimmunotherapy exhibited significantly superior PFS (7.5 vs. 4.8 months, HR =0.44, P=0.002) and OS (16.2 vs. 11.5 months, HR =0.44, P=0.005) (Figure 2C,2D), whereas TTF-1-positive patients (n=187) showed no significant survival differences (PFS: 8.0 vs. 7.3 months, HR =0.88, P=0.42; OS: 18.7 vs. 18.3 months, HR =0.86, P=0.44) (Figure 2E,2F). These results indicate that PD-L1-negative/TTF-1-negative lung adenocarcinoma patients derive substantial survival benefits from chemoimmunotherapy, whereas TTF-1-positive patients exhibit comparable outcomes with chemotherapy alone.

Figure 2 Kaplan-Meier curves in PD-L1-negative patients treated with chemoimmunotherapy and chemotherapy stratified by TTF-1 expression. (A) PFS in total population; (B) OS in total population; (C) PFS in TTF-1-negative cohort; (D) OS in TTF-1-negative cohort; (E) PFS in TTF-1-positive cohort; (F) OS in TTF-1-positive cohort. Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; TTF-1, thyroid transcription factor-1.

Chemoimmunotherapy vs. chemotherapy with different regimens stratified by TTF-1 expression

Based on the aforementioned findings, we further stratified the chemotherapy backbone agents in our study to clarify the role of TTF-1 in optimizing treatment options for PD-L1-negative advanced lung adenocarcinoma. The study encompassed four platinum-based treatment regimens: pemetrexed-based chemotherapy, pemetrexed-based chemoimmunotherapy, taxane-based chemotherapy, and taxane-based chemoimmunotherapy. In the TTF-1-negative cohort, those receiving taxane-based chemoimmunotherapy had the longest median PFS and OS, while patients receiving pemetrexed-based chemotherapy had the shortest median PFS and OS, with statistically significant differences (pemetrexed-based chemotherapy vs. pemetrexed-based chemoimmunotherapy vs. taxane-based chemotherapy vs. taxane-based chemoimmunotherapy; PFS: 4.6 vs. 7.2 vs. 6.2 vs. 8.2 months, P<0.001; OS: 8.2 vs. 15.6 vs. 13.7 vs. 19.8 months, P=0.001) (Figure 3A,3B). However, in the TTF-1-positive population, there were no significant differences in median PFS (P=0.28) and OS (P=0.74) among patients receiving the four treatment regimens (Figure 3C,3D). These results suggest that in PD-L1-negative lung adenocarcinoma patients, TTF-1-negative patients may derive greater survival benefits from taxane-based chemoimmunotherapy. In contrast, TTF-1-positive patients have limited benefits from immunotherapy, and pemetrexed-based chemotherapy may be a sufficient choice.

Figure 3 Kaplan-Meier curves in patients treated with pemetrexed or taxane-based chemoimmunotherapy and chemotherapy stratified by TTF-1 expression. (A) PFS in TTF-1-negative cohort; (B) OS in TTF-1-negative cohort; (C) PFS in TTF-1-positive cohort; (D) OS in TTF-1-positive cohort. CI, confidence interval; HR, hazard ratio; ICI, immune checkpoint inhibitor; OS, overall survival; PFS, progression-free survival; TTF-1, thyroid transcription factor-1.

Prognostic factors stratified by TTF-1 expression

Multivariate Cox proportional hazards models adjusted for age, performance status score, and hepatic metastasis (covariates selected based on SMD >0.1 and clinical relevance) were employed to identify prognostic determinants of PFS and OS in PD-L1-negative lung adenocarcinoma patients stratified by TTF-1 expression status. This adjustment ensured the reported HRs for therapeutic intervention variables (immunotherapy-containing regimen and chemotherapy backbone) reflected their independent effects beyond these key clinical confounders.

In the TTF-1-negative cohort (Table 2), immunotherapy-containing regimen (aHR =0.44, 95% CI: 0.24–0.81; P=0.008), chemotherapy backbone (taxane- vs. pemetrexed-based: aHR =0.45, 95% CI: 0.24–0.86; P=0.02), and ECOG PS score (aHR =0.36, 95% CI: 0.18–0.72; P=0.004) were independently associated with PFS. For OS, immunotherapy-containing regimen (aHR =0.48, 95% CI: 0.25–0.90; P=0.02) and ECOG-PS score (aHR =0.34, 95% CI: 0.16–0.70; P=0.004) retained prognostic significance, while chemotherapy backbone demonstrated borderline significance (aHR =0.51, 95% CI: 0.26–1.01; P=0.054).

Among TTF-1-positive patients (Table 3), age stratification (aHR =0.70, 95% CI: 0.50–0.98; P=0.04), ECOG-PS score (aHR =0.34, 95% CI: 0.22–0.52; P<0.001), and hepatic metastasis (aHR =1.82, 95% CI: 1.13–2.94; P=0.01) independently predicted PFS. For OS, ECOG-PS score (aHR =0.37, 95% CI: 0.22–0.60; P<0.001) and hepatic metastasis (aHR =3.05, 95% CI: 1.74–5.35; P<0.001) emerged as significant prognosticators. This section highlights a critical divergence in prognostic determinants based on TTF-1 expression. For TTF-1-negative PD-L1-negative lung adenocarcinoma, immunotherapy-containing regimen and ECOG-PS dominated survival outcomes, whereas in TTF-1-positive patients, hepatic metastasis and ECOG-PS were the primary drivers of prognosis, underscoring the biomarker’s role in therapeutic stratification.

Discussion

This study was the first to conduct a stratified analysis based on TTF-1 expression in PD-L1-negative lung adenocarcinoma populations, aiming to establish biomarker-guided precision treatment strategies. In this retrospective analysis, PD-L1-negative/TTF-1-negative patients treated with chemoimmunotherapy demonstrated significantly prolonged survival, with taxane-based regimens showing superior outcomes compared to pemetrexed-based regimens. Conversely, PD-L1-negative/TTF-1-positive patients exhibited comparable survival outcomes between chemoimmunotherapy and chemotherapy alone, with no significant prognostic impact from chemotherapy backbone selection (pemetrexed vs. taxane). This stratification model provides dual clinical decision-making implications for PD-L1-negative advanced lung adenocarcinoma: identifying immunotherapy-sensitive populations while guiding optimal chemotherapy backbone selection.

Previous studies have demonstrated that TTF-1-negative lung adenocarcinoma is associated with poorer prognosis, worse performance status, higher metastatic burden, and increased resistance to tyrosine kinase inhibitors (TKIs) and chemotherapy (10,19,20). Our findings corroborate these observations, revealing significantly shorter median PFS and OS in TTF-1-negative patients compared to TTF-1-positive counterparts (Figure S1), thereby confirming the prognostic value of TTF-1 expression in PD-L1-negative NSCLC.

A stratified balance assessment was performed to compare baseline covariates between chemotherapy and chemoimmunotherapy cohorts within TTF-1-defined subgroups (Table 1). All major prognostic variables exhibited SMDs <0.2, with no statistically significant intergroup imbalances (all P>0.05). Multivariable Cox regression analyses demonstrated minimal fluctuations in core HRs (<10% variation after adjustment), supporting robust covariate balance across analytical models. In alignment with the STRATOS Initiative guidelines (21) and recommendations by Austin et al. (22)—which caution against unnecessary propensity score matching (PSM) when subgroup covariates are well-balanced and sensitivity analyses yield stable results—this study concluded that PSM was nonessential in this analytical framework.

Previous studies have predominantly focused on the prognostic relevance of TTF-1 expression, with limited exploration of its predictive value in treatment selection. Katayama et al. (14) prospectively demonstrated that in advanced lung adenocarcinoma patients receiving pemetrexed-based chemoimmunotherapy, the TTF-1-positive subgroup achieved significantly superior median PFS compared to the TTF-1-negative subgroup (10.9 vs. 5.0 months; P=0.01). However, these findings only reflect prognostic stratification under specific therapeutic regimens. This limitation was addressed in the study by Nishioka et al., which revealed that TTF-1 expression status did not affect survival benefits from chemoimmunotherapy in PD-L1-positive populations (TPS ≥1%) (HR =1.12, P=0.31), suggesting that immunotherapy integration may neutralize the adverse prognostic impact of TTF-1 negativity (16,17). Notably, in the PD-L1 low-expression subgroup (1–49%), TTF-1-negative patients receiving chemoimmunotherapy showed significant prolongation of PFS compared to chemotherapy alone (6.0 vs. 4.1 months; P=0.007), while no statistically significant difference was observed in the TTF-1-positive group (7.6 vs. 6.4 months; P=0.054). Building upon this discovery, our analysis of the PD-L1-negative cohort further revealed that among patients with PD-L1-negative/TTF-1-positive status, the efficacy difference between chemoimmunotherapy and chemotherapy alone was minimal, whereas the TTF-1-negative subgroup demonstrated significant clinical benefit. This highlights the existence of immunotherapy-sensitive subpopulations within PD-L1-negative populations that can be identified through TTF-1 screening. Collectively, this evidence indicates that TTF-1 not only serves as a prognostic biomarker but also functions as a critical complementary indicator to PD-L1 testing, guiding precision treatment decisions.

PD-L1-negative tumors are conventionally termed immune “cold” tumors; however, the TTF-1-negative subset may paradoxically benefit from immunotherapy, suggesting distinct immunomodulatory mechanisms within the PD-L1-negative/TTF-1-negative tumor microenvironment. Serglycin (SRGN), an intracellular proteoglycan overexpressed in a subset of lung cancers, is positively associated with tumor aggressiveness (23). In TTF-1-negative lung adenocarcinoma, SRGN promotes stromal cell migration and fosters an immunosuppressive microenvironment by upregulating IL-6, IL-8, and CXCL1 (24). Notably, SRGN expression positively correlates with PD-L1 levels, and its downregulation in PD-L1-negative contexts may attenuate immunosuppressive effects on TTF-1-negative tumors. Furthermore, in PD-L1-negative NSCLC patients, the aggressive TTF-1-negative phenotype independently associates with elevated tumor mutational burden (TMB). This genomic instability may drive tumor-specific neoantigen generation, activating MHC-I-dependent CD8⁺ T-cell responses that bypass PD-L1-dependent immune evasion mechanisms (25).

This study, based on TTF-1 expression status, first revealed the differential efficacy of pemetrexed versus taxanes in PD-L1-negative advanced lung adenocarcinoma. Given that platinum-based doublet regimens containing pemetrexed/taxanes dominate clinical practice at our center (>90% utilization), with gemcitabine and vinorelbine being rarely used, we systematically compared the efficacies of these two regimens. Consistent with previous studies (26,27), chemotherapy selection (pemetrexed/taxanes) did not affect prognosis in TTF-1-positive patients (PFS: aHR =1.32, 95% CI: 0.94–1.87; OS: aHR =0.84, 95% CI: 0.53–1.31) (Table 3). In contrast, TTF-1-negative patients demonstrated superior clinical responses to taxane-based chemotherapy or chemoimmunotherapy compared to pemetrexed-based regimens (Figure 3). The enhanced sensitivity of TTF-1-negative lung adenocarcinoma to taxanes over pemetrexed may mechanistically stem from its phenotypic and behavioral resemblance to squamous cell carcinoma (28).

This study has several limitations. As a single-center retrospective clinical study, the findings may be influenced by selection biases inherent to single-institution treatment protocols, physician practice patterns, and patient population characteristics. Despite performing statistical balance testing on major clinical characteristics of enrolled patients, residual confounding factors might persist. Additionally, this study assessed TTF-1 using the SPT24 clone, whereas the guideline-recommended 8G7G3/1 clone shows better specificity and nuclear staining consistency (29). Although SPT24 has been widely validated in clinical practice, inter-clonal variability in staining performance may affect TTF-1 status classification. Future prospective trials will employ distinct TTF-1 clones (including 8G7G3/1 clone) to validate their predictive value in chemoimmunotherapy response, ensuring broader applicability.

Conclusions

TTF-1 expression may be a useful biomarker for predicting chemoimmunotherapy response in PD-L1-negative lung adenocarcinoma and aiding chemotherapy regimen selection, pending further validation. In this retrospective cohort, TTF-1-negative patients demonstrated improved survival with chemoimmunotherapy (especially taxane-based regimens) compared to chemotherapy alone, while TTF-1-positive patients showed no survival benefit from immunotherapy combinations. These findings provide a biomarker-driven rationale for personalized therapeutic strategies in precision oncology.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the REMARK reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-644/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-644/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-644/prf

Funding: This work was supported by Basic and Applied Basic Research Projects of Guangdong Province (No. 2021A1515220040).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-644/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of General Hospital of Southern Theater Command (approval No. NZLLKZ2024159), which waived the requirement for informed consent due to the anonymized use of clinical data.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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