The depths of PD-1 function within the tumor microenvironment beyond CD8+ T cells

Laba, Stephanie; Mallett, Grace; Amarnath, Shoba

doi:10.1016/j.semcancer.2021.05.022

Cited by 24 publications

(19 citation statements)

References 169 publications

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“…Th1 cells play an antitumor role by orchestrating immunity against tumor cells. Th1 cells enhance the generation and function of CD8 + T cells, prevent angiogenesis, promote the senescence of tumor cells, and protect effector cytotoxic T lymphocytes from exhaustion; thus, modulating the Th1 cell response may lead to effective immune-based therapy ( Basu et al, 2021 ; Laba et al, 2021 ; Renaude et al, 2021 ). Following differentiation, Th2 cells can produce IL-4, IL-5, IL-10, IL-13, and IL-17, not all of which are beneficial in cancer and contribute to tumor growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…Following differentiation, Th2 cells can produce IL-4, IL-5, IL-10, IL-13, and IL-17, not all of which are beneficial in cancer and contribute to tumor growth and metastasis. Simultaneously, infiltration of Th2 cells in the TME is usually connected with a poor prognosis in human cancers ( Basu et al, 2021 ; Laba et al, 2021 ; Renaude et al, 2021 ). In the present study, we found that HSF2 expression was negatively associated with the infiltration level of Th1 cells but positively correlated with the level of infiltrating Th2 cells in most tumor types.…”

Section: Discussionmentioning

confidence: 99%

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Pan-Cancer Integrated Analysis of HSF2 Expression, Prognostic Value and Potential Implications for Cancer Immunity

Chen

Fan

Liu

et al. 2022

Front. Mol. Biosci.

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Heat shock factor 2 (HSF2), a transcription factor, plays significant roles in corticogenesis and spermatogenesis by regulating various target genes and signaling pathways. However, its expression, clinical significance and correlation with tumor-infiltrating immune cells across cancers have rarely been explored. In the present study, we comprehensively investigated the expression dysregulation and prognostic significance of HSF2, and the relationship with clinicopathological parameters and immune infiltration across cancers. The mRNA expression status of HSF2 was analyzed by TCGA, GTEx, and CCLE. Kaplan-Meier analysis and Cox regression were applied to explore the prognostic significance of HSF2 in different cancers. The relationship between HSF2 expression and DNA methylation, immune infiltration of different immune cells, immune checkpoints, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed using data directly from the TCGA database. HSF2 expression was dysregulated in the human pan-cancer dataset. High expression of HSF2 was associated with poor overall survival (OS) in BRCA, KIRP, LIHC, and MESO but correlated with favorable OS in LAML, KIRC, and PAAD. The results of Cox regression and nomogram analyses revealed that HSF2 was an independent factor for KIRP, ACC, and LIHC prognosis. GO, KEGG, and GSEA results indicated that HSF2 was involved in various oncogenesis- and immunity-related signaling pathways. HSF2 expression was associated with TMB in 9 cancer types and associated with MSI in 5 cancer types, while there was a correlation between HSF2 expression and DNA methylation in 27 types of cancer. Additionally, HSF2 expression was correlated with immune cell infiltration, immune checkpoint genes, and the tumor immune microenvironment in various cancers, indicating that HSF2 could be a potential therapeutic target for immunotherapy. Our findings revealed the important roles of HSF2 across different cancer types.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pan-Cancer Integrated Analysis of HSF2 Expression, Prognostic Value and Potential Implications for Cancer Immunity

Chen

Fan

Liu

et al. 2022

Front. Mol. Biosci.

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“…Furthermore, Pazina et al encountered difficulties in the detection of any levels of PD-1 even in myeloma samples (165). A recent study proved that PD-1 mRNA and cytoplasmic PD-1 protein can be detected in NK cells, which suggests that surface PD-1 expression is inducible; hence, flow cytometry may provide variable data (213). There are data indicating the ominous role of the TME cellular compartment in PD-1/PD-L axis-related impairment of NK cells.…”

Section: Nk Cell Inhibitory Receptors In MMmentioning

confidence: 99%

Natural Killer Cells in the Malignant Niche of Multiple Myeloma

et al. 2022

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Natural killer (NK) cells represent a subset of CD3- CD7+ CD56+/dim lymphocytes with cytotoxic and suppressor activity against virus-infected cells and cancer cells. The overall potential of NK cells has brought them to the spotlight of targeted immunotherapy in solid and hematological malignancies, including multiple myeloma (MM). Nonetheless, NK cells are subjected to a variety of cancer defense mechanisms, leading to impaired maturation, chemotaxis, target recognition, and killing. This review aims to summarize the available and most current knowledge about cancer-related impairment of NK cell function occurring in MM.

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“…Owing to the detrimental role for anti-tumor immunity, most studies investigating the mechanisms underlying PD-1/PD-L1 blockade in cancer initially focused on the beneficial effects for CD8 + T cell cytotoxicity, due to disruption of inhibitory signaling on the T-cell side, and thereby increased anti-tumor function [ 144 ]. However, recent evidence suggests that the outcome of PD-1/PD-L1-blocking ICI therapy may also be conferred in large part by non-CD8 + T cells, comprising innate and adaptive immune cell types [ 145 ]. In particular, it has been demonstrated that the expression of PD-1 is not only confined to (CD8 + ) T cells, but also shows a significant expression on myeloid cells, B cells and NK cells, as well as on a variety of tumor cells [ 146 ].…”

Section: Treatment Of Metastatic Melanoma and Other Solid Tumors With...mentioning

confidence: 99%

“…While PD-1 expression has not been described on naïve CD4 + T helper cells, it has been reported on Treg [ 148 ] and T follicular helper cells (Tfh) [ 149 ] and is particularly observed in Th1 and Th2 cells upon activation in an inflammatory cytokine environment [ 145 , 150 ]. The important functional role of PD-1 for influencing CD4 + T-cell dependent immune responses has been demonstrated by Nagasaki and coworkers, who reported on the significance of a PD-1-mediated CD4 + T cell anti-tumor immunity in a mouse model of Hodgkin’s lymphoma, which has been abrogated in CD4 + T-cell deficient mice [ 150 ].…”

Section: Treatment Of Metastatic Melanoma and Other Solid Tumors With...mentioning

confidence: 99%

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

Kuske

Haist

Jung

et al. 2022

Cancers

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The approval of immune checkpoint inhibitors (ICI) that serve to enhance effector T-cell anti-tumor responses has strongly improved success rates in the treatment of metastatic melanoma and other tumor types. The currently approved ICI constitute monoclonal antibodies blocking cytotoxic T-lymphocyte-associated protein (CTLA)-4 and anti-programmed cell death (PD)-1. By this, the T-cell-inhibitory CTLA-4/CD80/86 and PD-1/PD-1L/2L signaling axes are inhibited. This leads to sustained effector T-cell activity and circumvents the immune evasion of tumor cells, which frequently upregulate PD-L1 expression and modulate immune checkpoint molecule expression on leukocytes. As a result, profound clinical responses are observed in 40–60% of metastatic melanoma patients. Despite the pivotal role of T effector cells for triggering anti-tumor immunity, mounting evidence indicates that ICI efficacy may also be attributable to other cell types than T effector cells. In particular, emerging research has shown that ICI also impacts innate immune cells, such as myeloid cells, natural killer cells and innate lymphoid cells, which may amplify tumoricidal functions beyond triggering T effector cells, and thus improves clinical efficacy. Effects of ICI on non-T cells may additionally explain, in part, the character and extent of adverse effects associated with treatment. Deeper knowledge of these effects is required to further develop ICI treatment in terms of responsiveness of patients to treatment, to overcome resistance to ICI and to alleviate adverse effects. In this review we give an overview into the currently known immunomodulatory effects of ICI treatment in immune cell types other than the T cell compartment.

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The depths of PD-1 function within the tumor microenvironment beyond CD8+ T cells

Cited by 24 publications

References 169 publications

Pan-Cancer Integrated Analysis of HSF2 Expression, Prognostic Value and Potential Implications for Cancer Immunity

Pan-Cancer Integrated Analysis of HSF2 Expression, Prognostic Value and Potential Implications for Cancer Immunity

Natural Killer Cells in the Malignant Niche of Multiple Myeloma

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

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