Effect of neoadjuvant chemotherapy on the immune microenvironment in non-small cell lung carcinomas as determined by
Edwin R Parra1, Pamela Villalobos2, Carmen Behrens3
1Department of Translational Molecular Pathology, Unit 951, The University of Texas MD Anderson Cancer Center, 2130 West Holcombe Blvd, Houston, TX, 77030, USA. erparra@mdanderson.org.
Background:
The clinical efficacy observed with inhibitors of programed cell death 1/programed cell death ligand 1 (PD-L1/PD-1) in cancer therapy has prompted studies to characterize the immune response in several tumor types, including lung cancer. However, the immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) is not yet fully characterized, and it may be therapeutically important. The aim of this retrospective study was to characterize and quantify PD-L1/PD-1 expression and tumor-associated immune cells (TAICs) in surgically resected NSCLCs from patients who received NCT or did not receive NCT (non-NCT).
Methods:
We analyzed immune markers in formalin-fixed, paraffin-embedded tumor tissues resected from 112 patients with stage II/III NSCLC, including 61 non-NCT (adenocarcinoma [ADC] = 33; squamous cell carcinoma [SCC] = 28) and 51 NCT (ADC = 31; SCC = 20). We used multiplex immunofluorescence to identify and quantify immune markers grouped into two 6-antibody panels: panel 1 included AE1/AE3, PD-L1, CD3, CD4, CD8, and CD68; panel 2 included AE1/AE3, PD1, granzyme B, FOXP3, CD45RO, and CD57.
Results:
PD-L1 expression was higher (> overall median) in NCT cases (median, 19.53%) than in non-NCT cases (median, 1.55%; P = 0.022). Overall, density of TAICs was higher in NCT-NSCLCs than in non-NCT-NSCLCs. Densities of CD3+ cells in the tumor epithelial compartment were higher in NCT-ADCs and NCT-SCCs than in non-NCT-ADCs and non-NCT-SCCs (P = 0.043). Compared with non-NCT-SCCs, NCT-SCCs showed significantly higher densities of CD3 + CD4+ (P = 0.019) and PD-1+ (P < 0.001) cells in the tumor epithelial compartment. Density of CD68+ tumor-associated macrophages (TAMs) was higher in NCT-NSCLCs than in non-NCT-NSCLCs and was significantly higher in NCT-SCCs than in non-NCT-SCCs. In NCT-NSCLCs, higher levels of epithelial T lymphocytes (CD3 + CD4+) and epithelial and stromal TAMs (CD68+) were associated with better outcome in univariate and multivariate analyses.
Conclusions:
NCT-NSCLCs exhibited higher levels of PD-L1 expression and T-cell subset regulation than non-NCT-NSCLCs, suggesting that NCT activates specific immune response mechanisms in lung cancer. These results suggest the need for clinical trials and translational studies of combined chemotherapy and immunotherapy prior to surgical resection of locally advanced NSCLC.
Insights
Neoadjuvant chemotherapy (NCT) in non-small cell lung cancer (NSCLC) increases programmed cell death ligand 1 (PD-L1) expression and tumor-associated immune cells. This suggests NCT activates immune responses, supporting combined chemotherapy and immunotherapy trials before surgery.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Programmed cell death 1/ligand 1 (PD-L1/PD-1) inhibitors show clinical efficacy in cancer therapy.
- The immunological profile of non-small cell lung carcinoma (NSCLC) treated with neoadjuvant chemotherapy (NCT) remains incompletely characterized.
- Understanding immune responses in NCT-treated NSCLC is crucial for therapeutic development.
Purpose of the Study:
- To characterize and quantify PD-L1/PD-1 expression in NSCLC patients who received NCT versus those who did not (non-NCT).
- To analyze the density of tumor-associated immune cells (TAICs) in relation to NCT status.
- To investigate the association between immune markers and patient outcomes.
Main Methods:
- Retrospective analysis of 112 stage II/III NSCLC tumor tissues (61 non-NCT, 51 NCT).
- Multiplex immunofluorescence using two 6-antibody panels to quantify PD-L1, PD-1, and various immune cell subsets (CD3, CD4, CD8, CD68, FOXP3, etc.).
- Comparison of immune marker expression and TAIC densities between NCT and non-NCT groups, including adenocarcinoma (ADC) and squamous cell carcinoma (SCC) subtypes.
Main Results:
- Higher PD-L1 expression (median 19.53% vs. 1.55%) and overall TAIC density observed in NCT cases compared to non-NCT cases.
- Increased densities of CD3+ cells, CD3+CD4+ T lymphocytes, PD-1+ cells, and CD68+ tumor-associated macrophages (TAMs) in the tumor microenvironment of NCT-treated NSCLCs, particularly in SCC.
- Higher levels of epithelial T lymphocytes (CD3+CD4+) and TAMs (CD68+) in NCT-NSCLCs were associated with better patient outcomes.
Conclusions:
- NCT upregulates PD-L1 expression and modulates T-cell subsets in NSCLC, indicating activation of specific anti-tumor immune responses.
- The findings suggest that NCT primes the tumor immune microenvironment, potentially enhancing sensitivity to immunotherapy.
- Clinical trials combining chemotherapy and immunotherapy prior to surgical resection for locally advanced NSCLC are warranted.
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