The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target

Zhao, Shuang G.; Lehrer, Jonathan; Chang, S. Laura; Das, Rajdeep; Erho, Nicholas; Liu, Yang; Sjöström, Martin; Den, Robert B.; Freedland, Stephen J.; Klein, Eric A.; Karnes, R. Jeffrey; Schaeffer, Edward M.; Xu, Melody J.; Speers, Corey; Nguyen, Paul L.; Ross, Ashley E.; Chan, June M.; Cooperberg, Matthew R.; Carroll, Peter R.; Davicioni, Elai; Fong, Lawrence; Spratt, Daniel E.; Feng, Felix Y.

doi:10.1093/jnci/djy141

Cited by 154 publications

(156 citation statements)

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“…Although the K‐M curve of M0 and M1 macrophages showed a similar trend, no statistical significance was found. Feng et al also reported the landscape of PCa patients based on several GEO databases, which is consistent to the current study. We found that M2 macrophage is a risk factor to PCa patients, Feng et al also reported that the higher ratio of M1 + M2/M0 indicated a poor prognosis.…”

Section: Discussionsupporting

confidence: 91%

The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

et al. 2019

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Prostate cancer (PCa), a severe health burden for males, accounts for the second frequent cancer and fifth tumor specific death cancer around the world. Several studies on tumor‐infiltrating immune cells (TIICs) have shown inconsistent and controversial results to PCa. We downloaded a gene expression matrix and clinical information from TCGA, and CIBERSORT was used to identify the proportion of TIICs. Wilcoxon's Sign Rank Test evaluated different gene expression levels in PCa and normal tissues. Kaplan‐Meier curves were used to evaluate the associations of TIICs and recurrence‐free survival (RFS). Finally, based on the preset P‐value of .05, the distribution of TIICs in 73 PCa tissues and 11 normal tissues was illustrated. Activated CD4 + T cells and M0 macrophages account for a high proportion in PCa tissues, while neutrophils and monocytes were found at a high density in normal tissues. Further results showed that the density of plasma cells, Treg cells and resting mast cells were associated with advanced PCa. Additionally, M2 macrophages affected the RFS of PCa patients, and AR was also involved. In the current study, we first evaluated the immune infiltration among PCa and revealed that M2 macrophages could predict the prognosis of PCa patients. Meanwhile, based on the LASSO regression analysis, we established a novel nomogram to assess the recurrence risk of PCa based on immune cell proportions and clinical features.

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Section: Discussionsupporting

confidence: 91%

The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

et al. 2019

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“…b Flow cytometry analysis shows deficiency of PPARG in macrophage suppresses M2-polarization and PD-L2 expression in TAMs and increases CD8+ CTLs in forestomach tumors (n = 6). c Schematic figure indicates esophageal carcinogenesis can be blocked by targeting TAMs infiltration via CCL2/CCR2 signaling (Target I) and M2 polarization via PPARG activation (Target II) related pathways, suggesting the critical role of PD-L2 in immune response [44]. Nonetheless, PD-L2 expression was independently associated with clinical response in pembrolizumab-treated (PD-1 mAb) patients with colorectal cancer, indicating that PD-L2 may be involved in response to PD-1 axis targeted therapies [45].…”

Section: Discussionmentioning

confidence: 99%

CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis

et al. 2020

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Background: The poor prognosis of esophageal squamous cell carcinoma (ESCC) highlights the need for novel strategies against this disease. Our previous study suggested the involvement of CCL2 and tumor associated macrophages (TAMs) in esophageal carcinogenesis. Despite the recognition of TAMs as a promising target for cancer treatment, mechanisms underlying its infiltration, activation and tumor-promotive function in ESCC remain unknown. Methods: Human esophageal tissue array and TCGA database were used to evaluate the clinical relevance of CCL2 and TAMs in ESCC. F344 rats and C57BL/6 mice were treated with N-nitrosomethylbenzylamine (NMBA) to establish orthotopic models of esophageal carcinogenesis. CCL2/CCR2 gene knockout mice and macrophage-specific PPARG gene knockout mice were respectively used to investigate the role of infiltration and polarization of TAMs in ESCC. CCL2-mediated monocyte chemotaxis was estimated in malignantly transformed Het-1A cells. THP-1 cells were used to simulate TAMs polarization in vitro. RNA-sequencing was performed to uncover the mechanism. Results: Increasing expression of CCL2 correlated with TAMs accumulation in esophageal carcinogenesis, and they both predicts poor prognosis in ESCC cohort. Animal studies show blockade of CCL2-CCR2 axis strongly reduces tumor incidence by hindering TAMs recruitment and thereby potentiates the antitumor efficacy of CD8 + T cells in the tumor microenvironment. More importantly, M2 polarization increases PD-L2 expression in TAMs, resulting in immune evasion and tumor promotion through PD-1 signaling pathway. Conclusion: This study highlights the role of CCL2-CCR2 axis in esophageal carcinogenesis. Our findings provide new insight into the mechanism of immune evasion mediated by TAMs in ESCC, suggesting the potential of TAMstargeted strategies for ESCC prevention and immunotherapy.

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“…However, a recent large study of 9393 PCa samples indeed disclosed an immune-related tumor cluster, with distinct patient outcome [121]. In this study, the proportion of different immune cell populations was associated with distinct distant metastasis-free survival and, interestingly, PD-L2 emerged as a promising prognostic biomarker (contrarily to PD-L1, like in BlCa and RCC) and predictive factor (of response to radiotherapy), which may also mean it can be a promising therapeutic target [121]. Genomic aberrations in PCa do divide 74% of the disease into several groups, mostly based on presence of specific gene fusions (ERG, ETV1/4, and FLI1) and mutations (SPOP, FOXA1 and IDH1); however, PCa belongs overall to the low mutational burden class of tumors.…”

Section: The Connection Between Genetic Epigenetic and Immune Landscmentioning

confidence: 99%

“…Also, the comonly observed deletion or mutation of PTEN contributes to the "immune desert" of PCa, since the latter activates IFN1-related pathways [120]. However, a recent large study of 9393 PCa samples indeed disclosed an immune-related tumor cluster, with distinct patient outcome [121]. In this study, the proportion of different immune cell populations was associated with distinct distant metastasis-free survival and, interestingly, PD-L2 emerged as a promising prognostic biomarker (contrarily to PD-L1, like in BlCa and RCC) and predictive factor (of response to radiotherapy), which may also mean it can be a promising therapeutic target [121].…”

Section: The Connection Between Genetic Epigenetic and Immune Landscmentioning

confidence: 99%

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

Lobo

Jerónimo

Henrique

2020

IJMS

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In the last years, we have witnessed remarkable advances in targeted therapies for cancer patients. There is a growing effort to either replace or reduce the dose of unspecific, systemic (chemo)therapies, given the associated short- and long-term side effects, by introducing more specific targeted therapies as single or combination agents. Due to the well-known implications of the immune system and epigenetic landscape in modulating cancer development, both have been explored as potential targets in several malignancies, including those affecting the genitourinary tract. As the immune system function is also epigenetically regulated, there is rationale for combining both strategies. However, this is still rather underexplored, namely in urological tumors. We aim to briefly review the use of immune therapies in prostate, kidney, bladder, and testicular cancer, and further describe studies providing supporting evidence on their combination with epigenetic-based therapies.

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The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target

Cited by 154 publications

References 50 publications

The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

The establishment of immune infiltration based novel recurrence predicting nomogram in prostate cancer

CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

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