VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer

Gao, Jianjun; Ward, John F.; Pettaway, Curtis A.; Shi, Lewis Zhichang; Subudhi, Sumit K.; Vence, Luis M.; Zhao, Hao; Chen, Jianfeng; Chen, Hong; Efstathiou, Eleni; Troncoso, Patricia; Allison, James P.; Logothetis, Christopher J.; Wistuba, Ignacio I.; Sepúlveda, Manuel A.; Sun, Jingjing; Wargo, Jennifer A.; Blando, Jorge; Sharma, Padmanee

doi:10.1038/nm.4308

Cited by 505 publications

(394 citation statements)

References 19 publications

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“…Indeed, we found that breast tumors infiltrated with TIM-3+ iTILs highly correlate with tumors positive for other checkpoint markers (PD-1, PD-L1 and LAG-3). Results are consistent with other reported studies and imply that the expression of multiple different immune checkpoints can occur during tumor progression, reflecting an ongoing battle between cancer cells and the immune system 38,39 . In our cohort, coexpression of TIM-3 with PD-1 and LAG-3 is associated with a particularly favorable prognosis, perhaps reflecting an underlying robust immune recognition of the cancer cells that is difficult for the tumor to evade.…”

Section: Discussionsupporting

confidence: 92%

“…Accumulating evidence suggests resistance to anti- CTLA-4 or anti-PD-1/PD-L1 inhibitors can occur in otherwise immunogenic cancers through compensatory upregulation of additional immune checkpoints 39,41 . TIM-3 has recently emerged as a target for cancer immunotherapy following pre-clinical studies suggesting its non-redundant functions in comparison to the better-characterized checkpoint markers PD-1/PD-L1, and efficacious treatment synergy when TIM-3 is targeted in combination with anti-PD1/PDL1 antibodies 26,27,42,43 .…”

Section: Discussionmentioning

confidence: 99%

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TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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“…In this regard, VISTA upregulation after CTLA-4 blockade with ipilimumab was recently reported in prostate carcinomas (32). In this study, VISTA was upregulated in tumor infiltrating immune cells, particularly in CD68+ tumor associated macrophages.…”

Section: Discussionmentioning

confidence: 85%

Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non–Small Cell Lung Cancer

Villarroel‐Espíndola

Datar

et al. 2018

Clinical Cancer Research

176

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Purpose Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human NSCLC. Experimental Design Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1 and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin+ tumor epithelial cells, CD3+ T-cells, CD4+ T-helper cells, CD8+ cytotoxic T-cells, CD20+ B-lymphocytes and CD68+ tumor-associated macrophages. We determined the association between the targets, clinico-pathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA was also performed. Results VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8+ T-cells and CD68+ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T-cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival. Conclusions VISTA is frequently expressed in human NSCLC and shows association with increased TILs, PD-1 axis markers, specific genomic alterations and outcome. These results support the immuno-modulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target.

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“…24 In prostate cancer, Gao et al have shown that while ipilimumab increased levels of tumor infiltrating T cells, it also increased levels of other compensatory inhibitory immune checkpoint molecules including PD-L1 and VISTA in tumor specimens from untreated and treated ipilimumab patients in a pre-surgical clinical trial. 25 These observations provide a rationale for combining ipilimumab and nivolumab in patients with prostate cancer, with the goal of targeting …”

Section: Combination Immunotherapy Strategiesmentioning

confidence: 99%

The Changing Therapeutic Landscape in Metastatic Prostate Cancer

Koletsky¹

2017

Oncology &Amp; Hematology Review (US)

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Over the past several years a number of novel and diverse agents have provided a significant clinical benefit for patients with metastatic castration-resistant prostate cancer including abiraterone, enzalutamide, sipuleucel-T, cabazitaxel, and radium-223. The early use of docetaxel or abiraterone at initiation of standard androgen deprivation therapy in patients with metastatic hormone-sensitive prostate cancer has also led to substantial improvements in overall survival. The identification of a truncating mutation in the androgen receptor (ARV7), a biomarker of resistance, may help clarify a more optimal sequencing of hormonal and chemotherapy-based therapies for patients with metastatic disease. The genomic landscape of both primary and metastatic prostate cancer has been an important focal point of translational research. The most widely studied pathways that affect tumorigenesis are the phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/protein kinase B (AKT) and poly ADP ribose polymerase (PARP) and DNA repair pathways. This review will highlight recent clinical trials which have had a major impact on the management of patients with metastatic disease with an emphasis on treatments driven by common genomic aberrations present in advanced prostate cancer.

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VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer

Cited by 505 publications

References 19 publications

TIM-3 expression in breast cancer

TIM-3 expression in breast cancer

Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non–Small Cell Lung Cancer

The Changing Therapeutic Landscape in Metastatic Prostate Cancer

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