Menopausal status influences the expression of programmed death (<scp>PD</scp>)‐1 and its ligand <scp>PD</scp>‐L1 on immune cells from the human female reproductive tract

Shen, Zheng; Rodriguez-García, Marta; Patel, Mickey V.; Barr, Fiona D.; Wira, Charles R.

doi:10.1111/aji.12532

Cited by 19 publications

(17 citation statements)

References 31 publications

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“…Another important finding from this study is the sex-associated difference in PD-L1 protein expression. PD-L1 is known to be expressed on a wide variety of immune cells and cancer cells and is partially regulated by estrogen and X-linked microRNAs [32,33]. Indeed, pre-treatment PD-L1 expression was recently shown to be predictive of response to BCG [34] included following pathological review (DMB and LC), using the WHO 2016 grading system [36].…”

Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Chenard

Jackson

Vidotto

et al. 2021

Preprint

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Non-muscle invasive bladder cancer (NMIBC) is significantly more common in men than women. However, female patients with NMIBC often present with more aggressive disease and do not respond as well to immunotherapy treatments. We hypothesized that sexual dimorphism in the tumor immune microenvironment (TIME) may contribute to the inferior clinical outcomes observed in female patients. To test this hypothesis, we interrogated the expression patterns of genes associated with specific immune cell types and immune regulatory pathways using tumor whole transcriptome profiles from male (n=357) and female (n=103) patients with NMIBC. High-grade tumors from female patients exhibited significantly increased expression of CD40, CTLA4, PDCD1, LAG3 and ICOS immune checkpoint genes. Based on the significant differences in expression profiles of these genes and the cell types that most commonly express these in the TIME, we evaluated the density and spatial distribution of CD8+Ki67+ (activated cytotoxic T cells), FoxP3+ (regulatory T cells), CD103+ (tissue resident T cells), CD163+ (M2-like tumor associated macrophages), CD79a+ (B cells), PD-L1+ (Programmed-Death Ligand-1) and PD-1+ cells using multiplexed immunofluorescence in an independent cohort of 332 patient tumors on a tissue microarray (n=259 males and n=73 females). Tumors from female patients showed significantly higher infiltration of CD163+ macrophages and PD-L1+ cells compared to tumors from male patients. Notably, increased infiltration of CD163+ macrophages and CD79a+ B cells independently associated with decreased recurrence free survival. Not only do these results have the potential to inform the rational utilization of immunomodulatory therapies based on the TIME of both male and female patients with NMIBC, these novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials.

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Section: Discussionmentioning

confidence: 99%

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Chenard

Jackson

Vidotto

et al. 2021

Preprint

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“…Female gender was associated with increased PDCD1LG2 expression in a study of hematopoietic neoplasms (44), similar to our findings in colorectal carcinoma. Sex hormones, such as estrogens, may upregulate cellular expression of immune checkpoint molecules, including the PDCD1 and its ligand CD274, in a variety of cell types (45,46). Taken together, our population-based data will likely inform further mechanistic studies to clarify potential roles of female sex hormones in the regulation of the immune checkpoint pathway in the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer

Masugi

Nishihara

Hamada

et al. 2017

Cancer Immunology Research

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Expression of the immune-checkpoint ligand CD274 (programmed cell death 1 ligand 1, PD-L1, from gene CD274) contributes to suppression of antitumor T cell–mediated immune response in various tumor types. However, the role of PDCD1LG2 (PD-L2, CD273, from gene PDCD1LG2) in the tumor microenvironment remains unclear. We hypothesized that tumor PDCD1LG2 expression might be inversely associated with lymphocytic reactions to colorectal cancer. We examined tumor PDCD1LG2 expression by immunohistochemistry in 823 colon and rectal carcinoma cases within two U.S.-nationwide cohort studies and categorized tumors into quartiles according to the percentage of PDCD1LG2–expressing carcinoma cells. We conducted multivariable ordinal logistic regression analysis to assess the associations of tumor PDCD1LG2 expression with Crohn’s-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, or tumor-infiltrating lymphocytes, controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long-interspersed nucleotide element-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Tumor PDCD1LG2 expression was inversely associated with Crohn’s-like lymphoid reaction (Ptrend = 0.0003). For a unit increase in the three-tiered ordinal categories of Crohn’s-like lymphoid reaction, a multivariable odds ratio in the highest (vs lowest) quartile of the percentage of PDCD1LG2–expressing tumor cells was 0.38 (95% confidence interval, 0.22–0.67). Tumor PDCD1LG2 expression was not associated with peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, or patient survival (Ptrend>0.13). Thus, tumor PDCD1LG2 expression is inversely associated with Crohn’s-like lymphoid reaction to colorectal cancer, suggesting a possible role of PDCD1LG2–expressing tumor cells in inhibiting the development of tertiary lymphoid tissues during colorectal carcinogenesis.

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“…The suppressive action of T cells is also dependent on PD-1 expression in Tregs, which is also increased by E2 (171). E2 also increased PD-L1 expression on T cells from the reproductive tract tissues (172,173). This provides another mechanism by which the adaptive component of the TME can have an estrogen dependent effect on the therapeutic efficacy of ICIs.…”

Section: Immune Checkpoint Modulationmentioning

confidence: 93%

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

2020

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Lung cancer mortality represents the leading cause of cancer related deaths in the United States and worldwide. Almost half of these deaths occur in female patients, making lung cancer the most common cause of cancer mortality in women with a higher annual mortality rate than breast, uterine, and ovarian cancers combined. The distinct epidemiological, histological and biological presentation of non-small cell lung cancer (NSCLC) in women combined with extensive preclinical data have demonstrated that the female sex hormone β-estradiol (E2) plays an important role in NSCLC tumorigenesis, prognosis, and treatment response. Estrogen receptors are widely expressed on stromal and immune cells, and estrogen-linked signaling pathways are known to be involved in regulating the response of both the innate and adaptive immune system. Immune evasion has been recognized as a "hallmark" of cancer and immunotherapy has re-defined standard of care treatment for NSCLC. Despite these advancements, the low response rates observed in patients treated with immune checkpoint inhibitors has led to a search for mediators of immunosuppression and ways to augment the action of these agents. We focus on emerging data describing sex differences that modulate immunotherapy efficacy in NSCLC, immunosuppressive properties of E2 that lead to a pro-tumor microenvironment (TME), and the translational potential of altering the immune microenvironment by targeting the estrogen signaling pathway. E2-induced modulation affects multiple cell types within the TME, including cancer-associated fibroblasts, tumor infiltrating myeloid cells, and tumor infiltrating lymphocytes, all of which interplay with lung tumor cells via E2 and estrogen receptor engagement, ultimately shaping the TME that may, in part, be responsible for the sex-based disparities observed in NSCLC. An improved understanding of the role of the estrogen pathway in NSCLC anti-cancer immunity may lead to novel therapeutic approaches for altering the TME to improve the efficacy of immunotherapy agents.

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Menopausal status influences the expression of programmed death (PD)‐1 and its ligand PD‐L1 on immune cells from the human female reproductive tract

Cited by 19 publications

References 31 publications

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Sexual dimorphism in outcomes of non-muscle invasive bladder cancer: a role of CD163+ M2 macrophages, B cells and PD-L1 immune checkpoint

Tumor PDCD1LG2 (PD-L2) Expression and the Lymphocytic Reaction to Colorectal Cancer

Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications

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