Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression

Papalampros, Alexandros; Vailas, Michail; Ntostoglou, Konstantinos; Chiloeches, Maria Lopez; Sakellariou, Stratigoula; Chouliari, Niki V; Samaras, Menelaos G; Veltsista, Paraskevi D; Theodorou, Sofia D.P.; Margetis, Aggelos; Bergonzini, Anna; Karydakis, Lysandros; Hasemaki, Natasha; Havaki, Sophia; Moustakas, Ioannis I; Chatzigeorgiou, Antonios; Karamitros, Timokratis; Patsea, Eleni; Kittas, Christos; Lazaris, Andreas C.; Felekouras, Evangelos; Gorgoulis, Vassilis G.; Frisan, Teresa; Pateras, Ioannis S.

doi:10.3390/cancers12071825

Cited by 16 publications

(17 citation statements)

References 48 publications

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“…Tolerance is exacerbated by TGF-β and IL-10 [ 18 ]. Taken together, senescent, anergic and exhausted T c cells often co-exist in the TME or circulation and simultaneously exert immunosuppressive effects [ 11 , 19 ]. The current limitations of check-point inhibitors suggest that targeting multiple dysfunctional T c cell states would be therapeutically beneficial.…”

Section: Exhaustion and Senescencementioning

confidence: 99%

“…Senescent T cells have been found in primary and metastatic solid tumor sites [ 19 , 20 , 21 , 22 , 23 ] as well as hematological malignancies [ 11 , 24 ]. T c senescence can be classified into two major cellular mechanisms which are however not entirely separated from one another: premature and replicative senescence.…”

Section: Mechanisms Of T Cell Senescence Inductionmentioning

confidence: 99%

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Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Liu

Stachura

et al. 2020

Cancers

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The inability of tumor-infiltrating T lymphocytes to eradicate tumor cells within the tumor microenvironment (TME) is a major obstacle to successful immunotherapeutic treatments. Understanding the immunosuppressive mechanisms within the TME is paramount to overcoming these obstacles. T cell senescence is a critical dysfunctional state present in the TME that differs from T cell exhaustion currently targeted by many immunotherapies. This review focuses on the physiological, molecular, metabolic and cellular processes that drive CD8+ T cell senescence. Evidence showing that senescent T cells hinder immunotherapies is discussed, as are therapeutic options to reverse T cell senescence.

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Section: Exhaustion and Senescencementioning

confidence: 99%

Section: Mechanisms Of T Cell Senescence Inductionmentioning

confidence: 99%

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Liu

Stachura

et al. 2020

Cancers

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“…Interestingly, the present study showed that PD‐L1 expression was significantly associated with SIRPα expression in ESCC. Previous studies showed that PD‐L1 is expressed in TAMs and plays a role in regulating their phagocytosis 41‐43 . Our IHC analysis suggested that SIRPα could be expressed in TAMs.…”

Section: Discussionmentioning

confidence: 49%

Clinical significance of signal regulatory protein alpha (SIRPα) expression in esophageal squamous cell carcinoma

Koga

Sakai

et al. 2021

Cancer Science

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Signal regulatory protein alpha (SIRPα) is a type I transmembrane protein that inhibits macrophage phagocytosis of tumor cells upon interaction with CD47, and the CD47‐SIRPα pathway acts as an immune checkpoint factor in cancers. This study aims to clarify the clinical significance of SIRPα expression in esophageal squamous cell carcinoma (ESCC). First, we assessed SIRPα expression using RNA sequencing data of 95 ESCC tissues from The Cancer Genome Atlas (TCGA) and immunohistochemical analytic data from our cohort of 131 patients with ESCC. Next, we investigated the correlation of SIRPα expression with clinicopathological factors, patient survival, infiltration of tumor immune cells, and expression of programmed cell death‐ligand 1 (PD‐L1). Overall survival was significantly poorer with high SIRPα expression than with low expression in both TCGA and our patient cohort (P < .001 and P = .027, respectively). High SIRPα expression was associated with greater depth of tumor invasion (P = .0017). Expression of SIRPα was also significantly correlated with the tumor infiltration of M1 macrophages, M2 macrophages, CD8+ T cells, and PD‐L1 expression (P < .001, P < .001, P = .03, and P < .001, respectively). Moreover, patients with SIRPα/PD‐L1 coexpression tended to have a worse prognosis than patients with expression of either protein alone or neither. Taken together, SIRPα indicates poor prognosis in ESCC, possibly through inhibiting macrophage phagocytosis of tumor cells and inducing suppression of antitumor immunity. Signal regulatory protein alpha should be considered as a potential therapeutic target in ESCC, especially if combined with PD‐1‐PD‐L1 blockade.

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“…This may be related to the Th1 cells among CD4 + T cells that activate CD8 + CTLs and promote the immune system to suppress tumor progression ( 5 ). A previous study explored the spatial distribution and functional status of T cells in different areas, including the tumor center, invasive front, normal parenchyma adjacent to the tumor, and tumor-positive and tumor-negative draining lymph nodes in PDAC ( 32 ). However, the current study explored only the infiltration of T cells in the PDAC tumor region and did not explore the functional status of T cells.…”

Section: Discussionmentioning

confidence: 99%

Large-Section Histopathology Can Better Indicate the Immune Microenvironment and Predict the Prognosis of Pancreatic Ductal Adenocarcinoma Than Small-Section Histopathology

et al. 2021

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Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor and is insensitive to radiotherapy and chemotherapy, as it is highly correlated with its complex tumor microenvironment (TME). A comprehensive description of PDAC’s immune microenvironment at the pathological level has not been reported, thus limiting its treatment. Previous studies have shown that large-section histopathology (LSH) can reveal the complete structure and margin of the tumor on a single slice and effectively reflect intratumoral heterogeneity. LSH, as opposed to classic small-section histopathology (SSH), can also be used to explore the infiltration state of immune cells in different regions. In the current study, EnVision immunohistochemical staining was used to explore the panoramic distribution of CD4-, CD8-, CD15-, CD20-, and CD56 (surface markers of helper T cells, cytotoxic T cells, neutrophils, B cells, and NK cells, respectively)-positive cells in 102 pairs of paraffin wax-embedded PDAC samples (LSH vs SSH) for the first time. These indicators were then analyzed, and correlations of clinicopathological characteristics with clinical prognoses were analyzed. The findings of this study show that LSH can effectively indicate more immune cells than SSH. Upregulated CD4, CD8, CD20, and CD56 or downregulated CD15 was correlated with a good prognosis in PDAC patients. However, analysis of SSH showed that only upregulated CD4 and CD8 can be used as indicators of a good prognosis. Multivariate Cox regression analysis showed that 7 variables, namely, pTNM stage (P=0.002), PDL1 expression (P=0.001), CDX2 expression (P=0.008), DPC4 expression (P=0.004), CD4 expression in LSH (P<0.001), CD8 expression in LSH (P=0.010) and CD15 expression in LSH (P=0.031), were significantly correlated with the prognosis of PDAC patients. The findings of this study indicate that LSH is an effective tool for a panoramic assessment of the immune microenvironment in pancreatic cancer patients.

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Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression

Cited by 16 publications

References 48 publications

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

Clinical significance of signal regulatory protein alpha (SIRPα) expression in esophageal squamous cell carcinoma

Large-Section Histopathology Can Better Indicate the Immune Microenvironment and Predict the Prognosis of Pancreatic Ductal Adenocarcinoma Than Small-Section Histopathology

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