The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies

Kumagai, Shogo; Togashi, Yosuke; Kamada, Tetsuo; Sugiyama, Eri; Nishinakamura, Hitomi; Takeuchi, Yoshiko; Kochin, Vitaly; Itahashi, Kota; Maeda, Yuka; Matsui, Shigeyuki; Shibahara, Takuma; Yamashita, Yasuho; Irie, Takuma; Tsuge, Ayaka; Fukuoka, Shota; Kawazoe, Akihito; Udagawa, Hibiki; Kirita, Keisuke; Aokage, Keiju; Ishii, Genichiro; Kuwata, Takeshi; Nakama, Kenta; Kawazu, Masahito; Ueno, Toshihide; Yamazaki, Naoya; Goto, Kōichi; Tsuboi, Masahiro; Mano, Hiroyuki; Doi, Toshihiko; Shitara, Kohei; Nishikawa, Hiroyoshi

doi:10.1038/s41590-020-0769-3

Cited by 520 publications

(457 citation statements)

References 56 publications

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“…Intriguingly, they demonstrated that PD-1 expression balance of CD8 T cells and Tregs could predict response to PD-1 blockade therapy. 52 The data discussed thus far has suggested that PD-1 suppresses the proliferative and immunosuppressive properties of Tregs. However, opposite effects have also been observed for PD-1 expression on Tregs.…”

Section: Roles Of Pd-1 Signaling In Distinct Cell Typesmentioning

confidence: 99%

“…23 Further, the effect of PD-1 blockade therapy in such patients can be determined using patient derived xenograft models. Lastly, given a recent study demonstrated that PD-1 expression balance of T cells could predict efficacy of PD-1 blockade therapy, 52 it would be valuable to determine the association between PD-1 expression balance of all PD-1-expressing cell subsets and clinical response of patients receiving PD-1 blockade therapy.…”

Section: Potential Biomarkers For Pd-1 Blockade Therapymentioning

confidence: 99%

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Non-canonical PD-1 signaling in cancer and its potential implications in clinic

Zha¹,

Wang²,

Shang

et al. 2021

J Immunother Cancer

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Programmed cell death 1 (PD-1)-based immunotherapy has revolutionized the treatment of various cancers. However, only a certain group of patients benefit from PD-1 blockade therapy and many patients succumb to hyperprogressive disease. Although, CD8 T cells and conventional T cells are generally considered to be the primary source of PD-1 in cancer, accumulating evidence suggests that other distinct cell types, including B cells, regulatory T cells, natural killer cells, dendritic cells, tumor-associated macrophages and cancer cells, also express PD-1. Hence, the response of patients with cancer to PD-1 blockade therapy is a cumulative effect of anti-PD-1 antibodies acting on a myriad of cell types. Although, the contribution of CD8 T cells to PD-1 blockade therapy has been well-established, recent studies also suggest the involvement of non-canonical PD-1 signaling in blockade therapy. This review discusses the role of non-canonical PD-1 signaling in distinct cell types and explores how the available knowledge can improve PD-1 blockade immunotherapy, particularly in identifying novel biomarkers and combination treatment strategies.

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Section: Roles Of Pd-1 Signaling In Distinct Cell Typesmentioning

confidence: 99%

Section: Potential Biomarkers For Pd-1 Blockade Therapymentioning

confidence: 99%

Non-canonical PD-1 signaling in cancer and its potential implications in clinic

Zha¹,

Wang²,

Shang

et al. 2021

J Immunother Cancer

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“…More recently, effector Treg cells (eTregs) have been identified as Treg cells that undergo high affinity TCR-antigen interactions associated with increased expression of IL-10 and inhibitory receptors (IRs), while Treg cells with low-affinity TCR interactions have increased levels of CD25 [27][28][29] . As such, there is evidence that these eTreg cells express the inhibitory receptor (IR) PD-1 [30][31][32][33] , and elevated levels of TIGIT, GITR, PD-L1, and CTLA-4 which contribute to the suppressive functions of the eTreg 22,27,29,34 . For effector T cells, expression of PD-1 is associated with repeated TCR stimulation 32,35,36 and the ability of this inhibitory receptor to antagonize costimulatory and TCR mediated signals 37,38 culminates in the loss of function and eventual deletion of the T cell 39,40 . This pathway is also relevant to Treg cell biology, and their expression of PD-L1 allows them to limit T cells that express PD-1 41,42 .…”

Section: Introductionmentioning

confidence: 99%

“…As such, there is evidence that these eTreg cells express the inhibitory receptor (IR) PD-1 [30][31][32][33] , and elevated levels of TIGIT, GITR, PD-L1, and CTLA-4 which contribute to the suppressive functions of the eTreg 22,27,29,34 . For effector T cells, expression of PD-1 is associated with repeated TCR stimulation 32,35,36 and the ability of this inhibitory receptor to antagonize costimulatory and TCR mediated signals 37,38 culminates in the loss of function and eventual deletion of the T cell 39,40 . This pathway is also relevant to Treg cell biology, and their expression of PD-L1 allows them to limit T cells that express PD-1 41,42 . However, although PD-1 is not essential for thymically or peripherally derived Treg cells 42,43 , other reports concluded that activation of PD-1 supported the formation of inducible (i)Treg cells 34,41,44,45 .…”

Section: Introductionmentioning

confidence: 99%

“…However, although PD-1 is not essential for thymically or peripherally derived Treg cells 42,43 , other reports concluded that activation of PD-1 supported the formation of inducible (i)Treg cells 34,41,44,45 . Moreover, recent studies have found that that blockade of the PD-1 pathway for cancer treatment results in increased numbers of PD-1 hi intratumor eTreg cells, associated with immune suppression, metastasis, and increased morbidity 32,33,45,46 .…”

Section: Introductionmentioning

confidence: 99%

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PD-L1 – PD-1 interactions limit effector Treg cell populations at homeostasis and during infection

Perry

Clark

Gullicksrud

et al. 2020

Preprint

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While much is known about the factors that promote the development of diverse Treg cell responses, less is known about the pathways that constrain Treg cell activities. The studies presented here reveal that at homeostasis there is a population of effector Treg cells that express PD-1, and that blockade of PD-L1 or loss of PD-1 results in increased Treg cell activity. In response to infection with the parasite T. gondii, the early production of IFN-γ results in widespread upregulation of PD-L1. Moreover, blockade of PD-L1, whole body deletion of PD-1, or lineage-specific deletion of PD-1 in Foxp3+ cells prevented the loss of the effector Treg cells but resulted in reduced pathogen specific CD4+ T cell responses during infection. Thus, at homeostasis basal PD-L1 expression constrains and tunes the pool of Treg cells, but during infection the upregulation of PD-L1 provides a mechanism to contract the Treg cell population required to maximize the development of pathogen specific CD4+ T cell responses.

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Immune microenvironment in patients with mismatch‐repair‐proficient oligometastatic colorectal cancer exposed to chemotherapy: the randomized MIROX GERCOR cohort study

et al. 2022

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In the era of immune checkpoint inhibitors, understanding the metastatic microenvironment of proficient mismatch repair/microsatellite stable (pMMR/MSS) colorectal cancer (CRC) is of paramount importance to both prognostication and the development of more effective novel therapies. In this study, primary and paired metastasis tissue samples were collected from patients with resectable metastatic CRC treated with adjuvant FOLFOX or peri‐operative chemotherapy in the MIROX phase III prospective study. In total, 74 cancer tissues were stained for CD3, CD8, Forkhead box protein 3 (FOXP3), programmed cell death protein‐1 (PD‐1, invasive front, stromal, intra‐epithelial compartments), and programmed death‐ligand 1 (PD‐L1, tumor, immune cells). The immune profiling of primary CRC had a limited value to predict the immune context of paired metastases for all markers but CD3+. The expression of CD8 and PD‐L1 was higher in metastases after neoadjuvant FOLFOX. In metastases, both CD3 T cells at the invasive front and PD‐L1 expressions on immune cells were predictive of better disease‐free survival. These results show that the effect of FOLFOX on modifying the immune microenvironment in resected CRC metastases and measurement of PD‐L1 expression and tumor‐infiltrating CD8 T cells in pMMR/MSS metastatic tissue samples could improve treatment strategies of metastatic CRC patients.

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The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies

Cited by 520 publications

References 56 publications

Non-canonical PD-1 signaling in cancer and its potential implications in clinic

Non-canonical PD-1 signaling in cancer and its potential implications in clinic

PD-L1 – PD-1 interactions limit effector Treg cell populations at homeostasis and during infection

Immune microenvironment in patients with mismatch‐repair‐proficient oligometastatic colorectal cancer exposed to chemotherapy: the randomized MIROX GERCOR cohort study

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