Inhibitors of the PD-1 Pathway in Tumor Therapy

LaFleur, Martin W.; Muroyama, Yuki; Drake, Charles G.; Sharpe, Arlene H.

doi:10.4049/jimmunol.1701044

Cited by 124 publications

(109 citation statements)

References 125 publications

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“…To eliminate or control this reservoir, effective cellular immune responses need to be restored, including CD8 ϩ CTL capable of recognizing and targeting HIV-1-infected CD4 ϩ T cells following virus latency reversal. The promise of PD-1/PD-L1-based therapies that reinvigorate cancer-specific CTL responses leading to improved survival (49,50) led us to investigate the use of PD-1 inhibitors in the setting of HIV-1 infection. The goal was to either enhance DC induction of de novo HIV-1-specific CTLs from naive T cell precursors or to improve the functional capacity of DC-activated memory T cells.…”

Section: Discussionmentioning

confidence: 99%

Contrasting Roles of the PD-1 Signaling Pathway in Dendritic Cell-Mediated Induction and Regulation of HIV-1-Specific Effector T Cell Functions

García-Bates

Palma

Shen

et al. 2019

J Virol

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Eliciting highly functional CD8 ϩ cytotoxic T lymphocyte (CTL) responses against a broad range of epitopes will likely be required for immunotherapeutic control of HIV-1 infection. However, the combination of CTL exhaustion and the ability of HIV-1 to rapidly establish CTL escape variants presents major hurdles toward this goal. Our previous work highlighted the use of monocyte-derived, mature, highinterleukin-12 (IL-12)-producing type 1 polarized dendritic cells (MDC1) to selectively induce more potent effector CTLs derived from naive, rather than memory, CD8 ϩ T cell precursors isolated from HIV-1-positive participants in the Multicenter AIDS Cohort Study. In this study, we report that these highly stimulatory antigen-presenting cells also express enhanced levels of the coinhibitory molecule programmed cell death ligand 1 (PD-L1), the ligand for PD-1, which is further upregulated upon subsequent stimulation with the CD4 ϩ T helper cell-derived factor CD40L. Interestingly, blocking the PD-1 signaling pathway during MDC1 induction of HIV-1-specific CTL responses inhibited the priming, activation, and differentiation of naive CD8 ϩ T cells into effector T cells expressing high levels of T-box transcription factor (T-bet hi ) and eomesodermin (Eomes ϩ ). In contrast, PD-1 blockade enhanced the overall magnitude of memory HIV-specific CTL responses and reversed the exhausted memory phenotype from a T-bet low /Eomes ϩ to a T-bet hi /Eomes ϩ phenotype. These results indicate that the PD-L1/PD-1 signaling pathway has a previously unappreciated dual role in the induction and regulation of HIV-1-specific CTL immunity, which is greatly determined by the context and differentiation stage of the responsive CD8 ϩ T cells. IMPORTANCE Targeting the PD-1/PD-L1 immune checkpoint axis with signaling inhibitors has proven to be a powerful immunotherapeutic strategy to enhance the functional quality and survival of existing antigen-specific effector T cells. However, our study demonstrates that the context and timing of PD-1 signaling in T cells greatly impact the outcome of the effector response. In particular, we show that PD-1 activation plays a positive role during the DC-mediated initiation stage of the primary T cell response, while it serves as an inhibitory mechanism during the effector phase of the response. Therefore, caution should be taken in the design of therapies that include targeting of the PD-1/PD-L1 signaling pathway in order to avoid potential negative impacts on the induction of de novo T cell responses. FIG 7 Percent of PD-1-positive CD8 ϩ and CD4 ϩ T cells during one round (12 days) of in vitro stimulation. MDC1 derived from HIV-1 ϩ participants were loaded with 18-mer HIV-1 Gag overlapping peptides and used as stimulators of T cells at a ratio of 1:10 (DC/T cells). CD8 ϩ (A) and CD4 ϩ (B) T cells were evaluated over time for PD-1 expression by flow cytometry. Results are from three separate donors.

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Section: Discussionmentioning

confidence: 99%

Contrasting Roles of the PD-1 Signaling Pathway in Dendritic Cell-Mediated Induction and Regulation of HIV-1-Specific Effector T Cell Functions

García-Bates

Palma

Shen

et al. 2019

J Virol

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“…One of the implications of adaptive immune resistance is that blocking the PD-1/PD-L1 interaction could lead to T cells reacquiring effector function-with subsequent tumor lysis and regression. This is indeed the case, as objective antitumor responses were observed in the very first trial of anti-PD-1 (Topalian et al 2012) and PD-1 or PD-L1 blocking antibodies are now U.S. Food and Drug Administration (FDA)-approved in about nine tumor types (LaFleur et al 2018).…”

Section: Pd-1/pd-l1 and Immune Escapementioning

confidence: 90%

“…One of the key molecular pathways involved in immune escape by tumors is the programmed death-1 (PD-1) pathway (LaFleur et al 2018). PD-1 is a cell surface marker originally identified from a cDNA library of T cells undergoing apoptosis (Ishida et al 1992).…”

Section: Pd-1/pd-l1 and Immune Escapementioning

confidence: 99%

Immunotherapy for Prostate Cancer

Venturini

Drake

2018

Cold Spring Harb Perspect Med

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Immunotherapy with agents that block immune checkpoints is a mainstay of therapy for several common tumor types; so far, prostate cancer is not among those treated using this method. The observed lack of activity in prostate cancer is not due to a lack of testing; several agents have been evaluated both alone and in combination. Although several combination strategies show some promise, it appears likely that a greater understanding of the prostate cancer tumor microenvironment and baseline immune response will be required to optimize future treatment strategies.

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“…38 The dissimilar results could also be due to differences in ICI activity, given that PD-1 inhibitors but not PD-L1 inhibitors block PD-L2 inhibitory signaling, but it is unclear whether this mechanistic difference translates into differences in clinical efficacy. 39 Several ongoing early-stage disease trials will further clarify the efficacy of ICIs in neoadjuvant and adjuvant regimens for TNBC (Table 3). Two key trials are investigating whether 1 year of adjuvant anti-PD-1/L1 therapy prolongs EFS or disease-free survival (DFS): the SWOG S1418/BR006 trial (NCT02954874) of pembrolizumab for patients with residual disease, and the A-brave trial (NCT02926196) of avelumab for patients with high-risk or residual disease.…”

Section: Early-stage Chemotherapy Combination Regimensmentioning

confidence: 99%

Role of Immunotherapy in Triple-Negative Breast Cancer

Keenan

Tolaney

2020

Journal of the National Comprehensive Cancer Network

387

298

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Immune checkpoint inhibitors (ICIs) have led to durable clinical remissions in many metastatic cancers. However, the single-agent efficacy of ICIs in breast cancer is low, including in triple-negative breast cancer (TNBC), which has several key characteristics that enhance ICI responses. Strategies to improve anticancer immune responses in TNBC are urgently needed to extend survival for patients with metastatic disease. This review presents ICI monotherapy response rates and discusses combination strategies with chemotherapy, targeted therapies, and novel immunotherapies. It concludes with a summary of immunotherapy biomarkers in TNBC and a call to action for future directions of research critical to advancing the efficacy of immunotherapy for patients with TNBC.Although response rates to ICIs are higher in TNBC than in hormone receptor-positive and HER2-positive breast cancers, the single-agent efficacy is still low, with monotherapy response rates ranging from approximately 5% in

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Inhibitors of the PD-1 Pathway in Tumor Therapy

Cited by 124 publications

References 125 publications

Contrasting Roles of the PD-1 Signaling Pathway in Dendritic Cell-Mediated Induction and Regulation of HIV-1-Specific Effector T Cell Functions

Contrasting Roles of the PD-1 Signaling Pathway in Dendritic Cell-Mediated Induction and Regulation of HIV-1-Specific Effector T Cell Functions

Immunotherapy for Prostate Cancer

Role of Immunotherapy in Triple-Negative Breast Cancer

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