The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder

Baras, Alexander S.; Drake, Charles G.; Liu, Jen‐Jane; Gandhi, Nilay; Kates, Max; Hoque, Mohammad O.; Meeker, Alan K.; Hahn, Noah M.; Taube, Janis M.; Schoenberg, Mark; Netto, George J.; Bivalacqua, Trinity J.

doi:10.1080/2162402x.2015.1134412

Cited by 143 publications

(129 citation statements)

References 42 publications

(32 reference statements)

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“…Our findings support prior studies suggesting that bladder tumor development and treatment response is characterized by changes in effector to regulatory T-cell ratios (25, 26). We also found that BCG leads to a substantial recruitment of CD4 + T cells and an increase in the CD4 + /FoxP3 + ratio, confirming prior work from the early 1990s that identified via IHC an influx of CD4 + cells in BCG treated patients (6, 7).…”

Section: Discussionsupporting

confidence: 92%

Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer

Kates¹,

Nirschl

Sopko³

et al. 2017

Cancer Immunology Research

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Intravesical BCG immunotherapy is the standard of care in treating non-muscle invasive bladder cancer, yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. Although prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T-cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer was characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. In contrast, treatment with intravesical BCG led to a large, transient rise in the CD4+ T-cell population in the urothelium, and was both more effective and immunogenic compared to intravesical chemotherapy. Whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that although BCG induces T-cell recruitment to the bladder, the T-cell phenotype does not markedly change, implying that combining T-cell activating agents with BCG might improve clinical activity.

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Section: Discussionsupporting

confidence: 92%

Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer

Kates¹,

Nirschl

Sopko³

et al. 2017

Cancer Immunology Research

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“…The hypothesis that the immune system also plays a role in the response of urothelial carcinoma to systemic chemotherapy is supported by a recent study by Baras et al, in which ratio of CD8 + TILs to CD25 + T regs was strongly associated with response to platinum-based neoadjuvant chemotherapy [268]. As mentioned above, it appears that in urothelial carcinoma the expression of checkpoint molecule PD-L1 on the cells of the immune infiltrate is more relevant in predicting response to PD-1 and PD-L1 inhibitors than expression on tumor cells [250,251].…”

Section: Tils In Genitourinary Carcinomasmentioning

confidence: 97%

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

Hendry

Salgado

Gevaert

et al. 2017

Advances in Anatomic Pathology

571

366

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Assessment of the immune response to tumors is growing in importance as the prognostic implications of this response are increasingly recognized, and as immunotherapies are evaluated and implemented in different tumor types. However, many different approaches can be used to assess and describe the immune response, which limits efforts at implementation as a routine clinical biomarker. In part 1 of this review, we have proposed a standardized methodology to assess tumor infiltrating lymphocytes (TILs) in solid tumors, based on the International Immuno-Oncology Biomarkers Working Group guidelines for invasive breast carcinoma. In part 2 of this review, we discuss the available evidence for the prognostic and predictive value of TILs in common solid tumors, including carcinomas of the lung, gastrointestinal tract, genitourinary system, gynecological system, and head and neck, as well as primary brain tumors, mesothelioma and melanoma. The particularities and different emphases in TIL assessment in different tumor types are discussed. The standardized methodology we propose can be adapted to different tumor types and may be used as a standard against which other approaches can be compared. Standardization of TIL assessment will help clinicians, researchers and pathologists to conclusively evaluate the utility of this simple biomarker in the current era of immunotherapy.

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“…115 Tumor cell PDL1 expression is observed in ~20% of muscle invasive urothelial carcinomas. 114,116 Increased tumor cell PD-L1 expression is generally associated with higher-stage disease, but an association with postcystectomy survival has not been consistently observed across multiple cohorts. 114,117–122 Many of the observed differences between these studies may be attributable to the use of different PD-L1 immunohistochemistry protocols, antibodies, scoring criteria, and sample sizes—again highlighting the perils of trying to compare across studies when there is a lack of assay harmonization and a unified scoring approach.…”

Section: Urothelial Carcinomamentioning

confidence: 99%

“…Notably, the immune contexture is also predictive of response to non-immune-based therapies such as conventional platinum-based neoadjuvant chemotherapy, whereby an increasing ratio of Treg to CD8 density is predictive of residual muscleinvasive tumor posttreatment. 116 …”

Section: Urothelial Carcinomamentioning

confidence: 99%

Implications of the tumor immune microenvironment for staging and therapeutics

et al. 2018

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Characterizing the tumor immune microenvironment enables the identification of new prognostic and predictive biomarkers, the development of novel therapeutic targets and strategies, and the possibility to guide first-line treatment algorithms. Although the driving elements within the tumor microenvironment of individual primary organ sites differ, many of the salient features remain the same. The presence of a robust antitumor milieu characterized by an abundance of CD8+ cytotoxic T-cells, Th1 helper cells, and associated cytokines often indicates a degree of tumor containment by the immune system and can even lead to tumor elimination. Some of these features have been combined into an ‘Immunoscore’, which has been shown to complement the prognostic ability of the current TNM staging for early stage colorectal carcinomas. Features of the immune microenvironment are also potential therapeutic targets, and immune checkpoint inhibitors targeting the PD-1/ PD-L1 axis are especially promising. FDA-approved indications for anti-PD-1/PD-L1 are rapidly expanding across numerous tumor types and, in certain cases, are accompanied by companion or complimentary PD-L1 immunohistochemical diagnostics. Pathologists have direct visual access to tumor tissue and in-depth knowledge of the histological variations between and within tumor types and thus are poised to drive forward our understanding of the tumor microenvironment. This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load. Characteristics of the local immune contexture and current pathology-related practices for specific tumor types are also addressed. In the future, characterization of the host antitumor immune response using multiplexed and multimodality biomarkers may help predict which patients will respond to immune-based therapies.

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The ratio of CD8 to Treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder

Cited by 143 publications

References 42 publications

Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer

Intravesical BCG Induces CD4+ T-Cell Expansion in an Immune Competent Model of Bladder Cancer

Implications of the tumor immune microenvironment for staging and therapeutics

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