The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes

Dammeijer, Floris; Gulijk, Mandy van; Mulder, Evalyn E A P; Lukkes, Melanie; Klaase, Larissa; Bosch, Thierry van den; Nimwegen, Menno van; Lau, Sai Ping; Latupeirissa, Kitty; Schetters, Sjoerd; Kooyk, Yvette van; Boon, Louis; Moyaart, Antien; Mueller, Yvonne M.; Katsikis, Peter D.; Eggermont, Alexander M.M.; Vroman, Heleen; Stadhouders, Ralph; Hendriks, Rudi W.; Thüsen, Jan von der; Grünhagen, Dirk J.; Verhoef, Cornelis; Hall, Thorbald van; Aerts, Joachim

doi:10.1016/j.ccell.2020.09.001

Cited by 378 publications

(316 citation statements)

References 57 publications

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“…In cancer, the interactions between PD-1 on cytotoxic T-lymphocytes and PD-L1 on tumor cells or tumor macrophages, NK cells, dendritic cells, and various other immune cells, result in an exhausted T-cell phenotype, rendering the immune system unable to detect and eliminate tumors via epigenetic changes within T-cells ( Figure 3) [168,171,[174][175][176][177][178][179][180][181][182]. In addition to the PD-1/PD-L1 interactions in the tumor microenvironment, the importance of these interactions were observed in the tumor draining lymph nodes, between the PD-1 expressing T-cells and PD-L1 expressing dendritic cells, which contribute to the anergic/exhausted T-cell phenotype [183]. Program cell death protein 2 (PD-L2) is the second ligand for PD-1 and is expressed on antigen presenting cells and melanoma cells.…”

Section: T-cell Dysfunctionmentioning

confidence: 99%

Overcoming Immune Evasion in Melanoma

Eddy

Chen

2020

IJMS

119

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Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is “curable” at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease.

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Section: T-cell Dysfunctionmentioning

confidence: 99%

Overcoming Immune Evasion in Melanoma

Eddy

Chen

2020

IJMS

119

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“…In tumors, CD8 cells exhibit direct killing activity against cancer cells, but they are seriously dependent on CD4 T cells for function and transition to memory cells (3–6). Although our current understanding of the functional space in the cancer-immunity cycle is that cancer antigen presentation primarily occurs in lymph nodes, the contribution of in situ cancer antigen presentation has not been be ruled out (7, 8).…”

Section: Introductionmentioning

confidence: 99%

“…Very few studies have directly addressed the role of peripheral antigen presentation in T cell responses (7, 9–12). In cancer three lines of evidence support that the TCRs are stimulated in situ within solid tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Third, right flank tumours that differ only in one MHCII neoantigen with left flank tumours are infiltrated by higher numbers of neoantigen-specific CD4 + T cells (15). DCs are scarce and immature within solid tumors and are generally considered to exert their primary effects in lymph nodes (2, 7, 8, 16, 17). Because structural tissue cells greatly outnumber professional antigen presenting cells, express immune genes (18) and can be induced to present antigens (12, 19), we hypothesized that they are required for local antigen presentation and antitumor immunity.…”

Section: Introductionmentioning

confidence: 99%

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Tumor MHCII immunity requires in situ antigen presentation by cancer-associated fibroblasts

Kerdidani

Goudevenou

Aerakis

et al. 2020

Preprint

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Author contributions: Conception and design study, M.T.; Development of methodology, M.T.;Acquisition of data, D.K., K.G., E.A., P.S., A.P. and M.T.; Analysis and interpretation of data, D.K., K.M.V., C.T., and M.T.; Providing human samples, I. ABSTRACTIn situ antigen presentation is required to sustain active proliferating CD4 + T cells in tumours and to help form memory CD8 + T cells, but the antigen presenting cells (APCs) and pathways involved remain elusive.Cancer associated fibroblasts (CAFs) are prominent stromal constituent of solid tumors. Current immunological dogma considers that CAFs facilitate tumour immune escape. A new subset of MHCII antigen presenting cancer-associated fibroblasts (apCAFs) has been described, but their function remains unknown. Here we report a previously unrecognized function of apCAFs in sustaining CD4 + T cells in primary human and murine lung tumours. In response to IFNγ and oxidative stress in tumours CAFs upregulated MHCII. Fibroblast-specific targeted ablation of MHCII induced a hypometabolic hypoproliferative state in CD4 + T cells, which impacted MHCII and MHCI immunity, accelerating tumor growth. apCAFs directly presented MHCII-peptide (MCHIIp) complexes to activate the TCRs of CD4 + T cell. Highthrough-put profiling and blocking assays unveiled a novel CAF to T cell communication pathway via complement 1q binding on membrane C1qbp. Thus, apCAFs sustain anti-tumor CD4 + T cells via MHCIIp-TCR and C1q-C1qbp binding. Our studies pave the way to the design of novel immunotherapeutic strategies that will harness apCAFs to help sustain T cells inside solid tumours. Statement of significanceThis work challenges the immunological dogma that dominant physiological significance in tumour specific immunity comes only through professional APCs, leading to the design of novel MHCII fibroblastdirected strategies to sustain endogenous or adoptively transferred CD4 + T cells within solid tumors.

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“…Further studies will be needed to test what signals are necessary for maintenance and migration of T cells in dLNs.The role of the dLN in immunotherapy remains uncertain. Expression of PD-L1on DCs is important for responses to anti-PD-L1 in some tumor models, and migratory DCs in tumor dLNs express both PD-L1 and the costimulatory receptor B7-2 (98).Moreover, PD-1 blockade can act in dLNs in transplant tumor models(99,100).Whether PD-1 blockade acts outside the TME in humans is not known, but therapeutic efficacy after anti-PD-1 treatment in patients is associated with changes in immune cell populations in the peripheral blood(101,102) and with the appearance of new T cell clones in the tumor after therapy(103)(104)(105). Our analyses of CD8 T cells from humans showed the presence of TSL-like cells in LNs and tumors.…”

mentioning

confidence: 99%

A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

Connolly

Kuchroo

Venkat

et al. 2021

Preprint

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Abstract“Stem-like” TCF1+ CD8+ T cells (TSL) are necessary for long-term maintenance of T cell responses and the efficacy of immunotherapy but, as tumors contain signals that should drive T-cell terminal-differentiation, how these cells are maintained in tumors remains unclear. We found that a small number of TCF1+ tumor-specific CD8+ T cells were present in tumors throughout development. Yet, most intratumoral T cells differentiated as tumors progressed, corresponding with an immunologic shift in the tumor microenvironment (TME) from “hot” to “cold”. By contrast, most tumor-specific CD8+ T cells in tumor-draining lymph nodes (dLNs) had functions and gene expression signatures similar to TSL from chronic LCMV infection and this population was stable over time, despite the changes in the TME. dLN T cells were the precursors of their more-differentiated intratumoral counterparts, and maintenance of TCF1 by intratumoral T cells required continuous migration from dLNs. Finally, TSL CD8 T cells were also present in LNs from lung adenocarcinoma patients, suggesting this population is also relevant in human disease. Thus, we propose that the dLN TSL reservoir has a critical function during tumor development in sustaining antitumor T cells during tumor development and protecting them from the terminal differentiation that occurs in the TME.

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The PD-1/PD-L1-Checkpoint Restrains T cell Immunity in Tumor-Draining Lymph Nodes

Cited by 378 publications

References 57 publications

Overcoming Immune Evasion in Melanoma

Overcoming Immune Evasion in Melanoma

Tumor MHCII immunity requires in situ antigen presentation by cancer-associated fibroblasts

A reservoir of stem-like CD8 T cells in the tumor-draining lymph node maintains the ongoing anti-tumor immune response

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