Induction of Progenitor Exhausted Tissue-Resident Memory CD8+ T Cells Upon Salmonella Typhi Porins Adjuvant Immunization Correlates With Melanoma Control and Anti-PD-1 Immunotherapy Cooperation

León‐Letelier, Ricardo A.; Castro-Medina, Daniel I; Badillo, O.; Tepale-Segura, Araceli; Huanosta-Murillo, Enrique; Aguilar-Flores, Cristina; León-Rodríguez, Saraí G. De; Mantilla, Alejandra; Fuentes‐Pananá, Ezequiel M.; López-Macías, Constantino; Bonifaz, Laura C.

doi:10.3389/fimmu.2020.583382

Cited by 13 publications

(12 citation statements)

References 61 publications

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“…Progenitor exhausted T cells are long-lived with stem-like properties. On the other hand, terminally exhausted T cells are short-lived, which is considered as a temporary effect in eliminating tumor cells [ 40 , 41 ]. Reversing T cell exhaustion by blocking the PD-1/PD-L1 pathway is a common strategy to control tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer

Kuo,

Hsieh

et al. 2024

J Biomed Sci

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Background Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor expressed on the surface of T cells. High expression of PD-1 leads to T-cell dysfunction in the tumor microenvironment (TME). However, the mechanism of intracellular trafficking and plasma membrane presentation of PD-1 remains unclear. Methods Multiple databases of lung cancer patients were integratively analyzed to screen Rab proteins and potential immune-related signaling pathways. Imaging and various biochemical assays were performed in Jurkat T cells, splenocytes, and human peripheral blood mononuclear cells (PBMCs). Rab37 knockout mice and specimens of lung cancer patients were used to validate the concept. Results Here, we identify novel mechanisms of intracellular trafficking and plasma membrane presentation of PD-1 mediated by Rab37 small GTPase to sustain T cell exhaustion, thereby leading to poor patient outcome. PD-1 colocalized with Rab37-specific vesicles of T cells in a GTP-dependent manner whereby Rab37 mediated dynamic trafficking and membrane presentation of PD-1. However, glycosylation mutant PD-1 delayed cargo recruitment to the Rab37 vesicles, thus stalling membrane presentation. Notably, T cell proliferation and activity were upregulated in tumor-infiltrating T cells from the tumor-bearing Rab37 knockout mice compared to those from wild type. Clinically, the multiplex immunofluorescence-immunohistochemical assay indicated that patients with high Rab37+/PD-1+/TIM3+/CD8+ tumor infiltrating T cell profile correlated with advanced tumor stages and poor overall survival. Moreover, human PBMCs from patients demonstrated high expression of Rab37, which positively correlated with elevated levels of PD-1+ and TIM3+ in CD8+ T cells exhibiting reduced tumoricidal activity. Conclusions Our results provide the first evidence that Rab37 small GTPase mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion, and the tumor promoting function of Rab37/PD-1 axis in T cells of TME in lung cancer. The expression profile of Rab37high/PD-1high/TIM3high in tumor-infiltrating CD8+ T cells is a biomarker for poor prognosis in lung cancer patients.

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Section: Discussionmentioning

confidence: 99%

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer

Kuo,

Hsieh

et al. 2024

J Biomed Sci

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“…Tissue resident memory CD103+ CD8 + T cells residing in the non-lymphoid tissues have shown to provide local immunosurveillance and enhanced immune responses in melanoma, lung and breast tumours (183)(184)(185)(186)(187). Moreover, melanoma patients with higher resident T cell population responded better to anti-PD-1 immunotherapy with improved survival (188,189). However, what is still unclear is how are tissue resident memory CD8 + T cells primed (Figure 2) and whether there is a distinct population of DCs required to activate them.…”

Section: Discussionmentioning

confidence: 99%

Control of Dendritic Cell Function Within the Tumour Microenvironment

2022

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The tumour microenvironment (TME) presents a major block to anti-tumour immune responses and to effective cancer immunotherapy. The inflammatory mediators such as cytokines, chemokines, growth factors and prostaglandins generated in the TME alter the phenotype and function of dendritic cells (DCs) that are critical for a successful adaptive immune response against the growing tumour. In this mini review we discuss how tumour cells and the surrounding stroma modulate DC maturation and trafficking to impact T cell function. Fibroblastic stroma and the associated extracellular matrix around tumours can also provide physical restrictions to infiltrating DCs and other leukocytes. We discuss interactions between the inflammatory TME and infiltrating immune cell function, exploring how the inflammatory TME affects generation of T cell-driven anti-tumour immunity. We discuss the open question of the relative importance of antigen-presentation site; locally within the TME versus tumour-draining lymph nodes. Addressing these questions will potentially increase immune surveillance and enhance anti-tumour immunity.

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“…Another promising avenue for immunopeptide-based immunotherapies is in combination with immune checkpoint inhibitors (ICI) with the potential for synergism as with anti-PD-1 immunotherapy [ 118 ]. Taking into account that ICI is mostly effective in the presence of tumor infiltrating lymphocytes, a prior immunization that can efficiently induce T cell tumor migration would enhance the efficiency of ICI therapy [ 119 , 120 ]. All things considered, the immunopeptidome field has crucial relevance for cancer interception.…”

Section: Discussionmentioning

confidence: 99%

Mining the Immunopeptidome for Antigenic Peptides in Cancer

León‐Letelier

Katayama

Hanash

2022

Cancers

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Although harnessing the immune system for cancer therapy has shown success, response to immunotherapy has been limited. The immunopeptidome of cancer cells presents an opportunity to discover novel antigens for immunotherapy applications. These neoantigens bind to MHC class I and class II molecules. Remarkably, the immunopeptidome encompasses protein post-translation modifications (PTMs) that may not be evident from genome or transcriptome profiling. A case in point is citrullination, which has been demonstrated to induce a strong immune response. In this review, we cover how the immunopeptidome, with a special focus on PTMs, can be utilized to identify cancer-specific antigens for immunotherapeutic applications.

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Induction of Progenitor Exhausted Tissue-Resident Memory CD8+ T Cells Upon Salmonella Typhi Porins Adjuvant Immunization Correlates With Melanoma Control and Anti-PD-1 Immunotherapy Cooperation

Cited by 13 publications

References 61 publications

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer

Rab37 mediates trafficking and membrane presentation of PD-1 to sustain T cell exhaustion in lung cancer

Control of Dendritic Cell Function Within the Tumour Microenvironment

Mining the Immunopeptidome for Antigenic Peptides in Cancer

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