Stromal PD-L1–Positive Regulatory T cells and PD-1–Positive CD8-Positive T cells Define the Response of Different Subsets of Non–Small Cell Lung Cancer to PD-1/PD-L1 Blockade Immunotherapy

Wu, Si-Pei; Liao, Ri-Qiang; Tu, Hai‐Yan; Wang, Wenjun; Dong, Zhong‐Yi; Huang, Shu‐Mei; Guo, Wenbing; Gou, Lan-ying; Sun, Huihui; Zhang, Qi; Xie, Zhi; Yan, Li; Su, Jian; Yang, Jing; Zhong, Wen‐Zhao; Zhang, Xuchao; Wu, Yi‐Long

doi:10.1016/j.jtho.2017.11.132

Cited by 130 publications

(97 citation statements)

References 40 publications

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“…Various studies have indicated that tumor expression of PD-L1 predicts overall survival, PFS, and treatment responses in patients receiving immune therapy for advanced NSCLC. [31][32][33] Similarly, we found that strong PD-L1 expression predicted a poor response to EGFR-TKI therapy, consistent with a recent report by Soo et al 22 However, other investigators have drawn conflicting conclusions. Lin et al 34 reported an association of PD-L1 expression with better PFS in EGFR mutation-positive patients treated with EGFR-TKIs (16.5 versus 8.6 months (PD-L1-negative), p ¼ 0.001).…”

Section: Discussionsupporting

confidence: 89%

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation

Dong

Xie

et al. 2018

Journal of Thoracic Oncology

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110

109

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Section: Discussionsupporting

confidence: 89%

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation

Dong

Xie

et al. 2018

Journal of Thoracic Oncology

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110

109

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“…These clinical features were faithfully recapitulated in early tumors in the orthotopic HKP1 model, leading us to utilize this model to target the PD-1/PD-L1 axis in early-stage lung cancer. Indeed, expression of PD-L1 in tumor cells and infiltrating immune cells and PD-1 in tumor-infiltrating T cells has been associated with responsiveness to blockade of the PD-1/PD-L1 immune checkpoint in NSCLC across the spectrum of the disease (8,9,(29)(30)(31)(32). Anti-PD-1 monotherapy yielded significant tumor control and improved survival in mice, which was associated with a robust antitumor immune response, as revealed by enhanced proliferation of T cell subsets and increased expression of effector cytokines by infiltrated CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival

Markowitz¹,

Havel²,

Crowley³

et al. 2018

JCI Insight

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Success of immune checkpoint inhibitors in advanced non-small-cell lung cancer (NSCLC) has invigorated their use in the neoadjuvant setting for early-stage disease. However, the cellular and molecular mechanisms of the early immune responses to therapy remain poorly understood. Through an integrated analysis of early-stage NSCLC patients and a Kras mutant mouse model, we show a prevalent programmed cell death 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) axis exemplified by increased intratumoral PD-1+ T cells and PD-L1 expression. Notably, tumor progression was associated with spatiotemporal modulation of the immune microenvironment with dominant immunosuppressive phenotypes at later phases of tumor growth. Importantly, PD-1 inhibition controlled tumor growth, improved overall survival, and reprogrammed tumor-associated lymphoid and myeloid cells. Depletion of T lymphocyte subsets demonstrated synergistic effects of those populations on PD-1 inhibition of tumor growth. Transcriptome analyses revealed T cell subset-specific alterations corresponding to degree of response to the treatment. These results provide insights into temporal evolution of the phenotypic effects of PD-1/PD-L1 activation and inhibition and motivate targeting of this axis early in lung cancer progression.

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“…Tumor-infiltrating lymphocyte analysis of patients reveals that PD-1 þ CD8 þ T cells play a critical role in antitumor immune responses and that they could be a biomarker to predict antitumor responses of immune checkpoint inhibitors (10)(11)(12). However, systemic immune responses comprising of CD62L low CD44 þ CD69 þ CD90 þ CD27 low Tbet þ CD4 þ T cells are required to establish antitumor immunity and subsequently eradicate tumors in murine models (13).…”

Section: Introductionmentioning

confidence: 99%

“…Thus, CD4 þ T-cell help could enhance the cancer immunity cycle. CD4 þ T cells play an important role in antitumor immunity of murine models, and CD4 þ T cells that recognize cancer neoepitopes have been identified in melanoma (5,8,11,12). CD4 þ T cells in the peripheral blood correlate with clinical response to PD-1 blockade in patients with melanoma (13).…”

Section: Introductionmentioning

confidence: 99%

CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy

Kagamu

Kitano

Yamaguchi

et al. 2020

Cancer Immunology Research

174

159

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◥ Accumulating evidence indicates that CD8 þ T cells in the tumor microenvironment and systemic CD4 þ T-cell immunity play an important role in mediating durable antitumor responses. We longitudinally examined T-cell immunity in the peripheral blood of patients with non-small lung cancer and found that responders had significantly (P < 0.0001) higher percentages of effector, CD62L low CD4 þ T cells prior to PD-1 blockade. Conversely, the percentage of CD25 þ FOXP3 þ CD4 þ T cells was significantly (P ¼ 0.034) higher in nonresponders. We developed a formula, which demonstrated 85.7% sensitivity and 100% specificity, based on the percentages of CD62L low CD4 þ T cells and CD25 þ FOXP3 þ cells to predict nonresponders. Mass cytometry analysis revealed that the CD62L low CD4 þ T-cell subset expressed T-bet þ , CD27 À , FOXP3 À , and CXCR3 þ , indicative of a Th1 subpopulation. CD62L low CD4 þ T cells significantly correlated with effector CD8 þ T cells (P ¼ 0.0091) and with PD-1 expression on effector CD8 þ T cells (P ¼ 0.0015). Gene expression analysis revealed that CCL19, CLEC-2A, IFNA, IL7, TGFBR3, CXCR3, and HDAC9 were preferentially expressed in CD62L low CD4 þ T cells derived from responders. Notably, longterm responders, who had >500-day progression-free survival, showed significantly higher numbers of CD62L low CD4 þ T cells prior to PD-1 blockade therapy. Decreased CD62L low CD4 þ T-cell percentages after therapy resulted in acquired resistance, with longterm survivors maintaining high CD62L low CD4 þ T-cell percentages. These results pave the way for new treatment strategies for patients by monitoring CD4 þ T-cell immune statuses in their peripheral blood.

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Stromal PD-L1–Positive Regulatory T cells and PD-1–Positive CD8-Positive T cells Define the Response of Different Subsets of Non–Small Cell Lung Cancer to PD-1/PD-L1 Blockade Immunotherapy

Abstract: Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC.

Cited by 130 publications

References 40 publications

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation

Immune reprogramming via PD-1 inhibition enhances early-stage lung cancer survival

CD4+ T-cell Immunity in the Peripheral Blood Correlates with Response to Anti-PD-1 Therapy

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