Dataset Information

Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC.

ABSTRACT:

Introduction

The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoint blockade.

Methods

Genomic, transcriptomic, and immune profiling data of 511 patients treated with neoadjuvant chemotherapy followed by surgery (NCT) versus upfront surgery (US) were compared with determined differential characteristics of the IMEs derived from whole-exome sequencing (NCT = 18; US = 73), RNA microarray (NCT = 45; US = 202), flow cytometry (NCT = 17; US = 39), multiplex immunofluorescence (NCT = 10; US = 72), T-cell receptor sequencing (NCT = 16 and US = 63), and circulating cytokines (NCT = 18; US = 73).

Results

NCT was associated with increased infiltration of cytotoxic CD8⁺ T cells and CD20⁺ B cells. Moreover, NCT was associated with increases in CD8⁺CD103⁺ and CD4⁺CD103⁺PD-1⁺TIM3^- tissue resident memory T cells. Gene expression profiling supported memory function of CD8⁺ and CD4⁺ T cells. However, NCT did not affect T-cell receptor clonality, richness, or tumor mutational burden. Finally, NCT was associated with decreased plasma BDNF (TrkB) at baseline and week 4 after surgery.

Conclusions

Our study supports that, in the context of resectable NSCLC, neoadjuvant chemotherapy promotes antitumor immunity through T and B cell recruitment in the IME and through a phenotypic change toward cytotoxic and memory CD8⁺ and CD4⁺ memory helper T cells.

SUBMITTER: Gaudreau PO

PROVIDER: S-EPMC7775914 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC.

Gaudreau Pierre-Olivier PO Negrao Marcelo V MV Mitchell Kyle G KG Reuben Alexandre A Corsini Erin M EM Li Jun J Karpinets Tatiana V TV Wang Qi Q Diao Lixia L Wang Jing J Federico Lorenzo L Parra-Cuentas Edwin R ER Khairullah Roohussaba R Behrens Carmen C Correa Arlene M AM Gomez Daniel D Little Latasha L Gumbs Curtis C Kadara Humam N HN Fujimoto Junya J McGrail Daniel J DJ Vaporciyan Ara A AA Swisher Stephen G SG Walsh Garrett G Antonoff Mara B MB Weissferdt Annikka A Tran Hai H Roarty Emily E Haymaker Cara C Bernatchez Chantale C Zhang Jianhua J Futreal P Andrew PA Wistuba Ignacio I II Cascone Tina T Heymach John V JV Sepesi Boris B Zhang Jianjun J Gibbons Don L DL

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20201021 1

<h4>Introduction</h4>The combination of programmed cell death protein-1 or programmed death-ligand 1 immune checkpoint blockade and chemotherapy has revolutionized the treatment of advanced NSCLC, but the mechanisms underlying this synergy remain incompletely understood. In this study, we explored the relationships between neoadjuvant chemotherapy and the immune microenvironment (IME) of resectable NSCLC to identify novel mechanisms by which chemotherapy may enhance the effect of immune checkpoi ...[more]

PMID: 33096269

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Project description:BackgroundA single-agent of anti programmed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) therapy has been explored for resectable lung cancer before surgery. However, the effectiveness and safety of neoadjuvant programmed cell death 1 (PD-1) blockade combined with chemotherapy have not been published.MethodsTwenty-one consecutive patients with potentially resectable squamous cell carcinoma of the lung who received neoadjuvant therapy followed by surgery in Beijing Cancer Hospital were included in this study. Eight patients received two cycles of neoadjuvant platinum-based doublet chemotherapy combined with anti-programmed cell death 1 (anti-PD-1) therapy, while 13 patients received two cycles of neoadjuvant platinum-based doublet chemotherapy only. Chest computed tomography was repeated before neoadjuvant treatment and surgery. Adverse events were monitored. The major pathological response (MPR) rate was determined after surgery. Selected specimens were sent for immunohistochemical and multiplex immunofluorescence analyses, and T-cell receptor DNA sequencing.ResultsCompared with neoadjuvant chemotherapy alone, the combination of PD-1 blockade and chemotherapy increased the pathological complete response rate (37.5% vs. 7.69%) and MPR rate (50% vs. 38.46%). The pathological and radiological evaluations are not consistent. No unknown adverse effects were reported for all the patients. More tumor infiltrating lymphocytes were observed in patients who received PD-1 blockade. No unknown pathological features associated with PD-1 blockade were found. Immune suppression in the peritumoral spaces around the residual tumor cells was observed. The amino acid sequences of the T-cell receptors are not significantly shared among the patients.ConclusionsThe combination of neoadjuvant chemotherapy and PD-1 blockade is safe and feasible, and might indicate an increased MPR and pathological complete response rate. More investigations are needed for the best combination of the neoadjuvant therapy.

Project description:BackgroundNeoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non-small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings.MethodsIn this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients.ResultsThe median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P = 0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group.ConclusionsIn patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.).

Dataset Information

Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC.

Introduction

Methods

Results

Conclusions

Publications

Neoadjuvant Chemotherapy Increases Cytotoxic T Cell, Tissue Resident Memory T Cell, and B Cell Infiltration in Resectable NSCLC.

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