TY - JOUR
T1 - Effect of neoadjuvant chemotherapy on the immune microenvironment in non-small cell lung carcinomas as determined by multiplex immunofluorescence and image analysis approaches
AU - Parra, Edwin R.
AU - Villalobos, Pamela
AU - Behrens, Carmen
AU - Jiang, Mei
AU - Pataer, Apar
AU - Swisher, Stephen G.
AU - William, William N.
AU - Zhang, Jiexin
AU - Lee, Jack
AU - Cascone, Tina
AU - Heymach, John V.
AU - Forget, Marie Andrée
AU - Haymaker, Cara
AU - Bernatchez, Chantale
AU - Kalhor, Neda
AU - Weissferdt, Annikka
AU - Moran, Cesar
AU - Zhang, Jianjun
AU - Vaporciyan, Ara
AU - Gibbons, Don L.
AU - Sepesi, Boris
AU - Wistuba, Ignacio I.
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/6/6
Y1 - 2018/6/6
N2 - 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.
AB - 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.
KW - Adenocarcinoma
KW - Epithelial compartment
KW - Squamous cell carcinoma
KW - Stromal compartment
KW - Survival
KW - T cells
KW - Tumor compartments
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U2 - 10.1186/s40425-018-0368-0
DO - 10.1186/s40425-018-0368-0
M3 - Article
C2 - 29871672
AN - SCOPUS:85048114656
SN - 2051-1426
VL - 6
JO - Journal for immunotherapy of cancer
JF - Journal for immunotherapy of cancer
IS - 1
M1 - 48
ER -