Association of HIV Status With Local Immune Response to Anal Squamous Cell Carcinoma

Yanik, Elizabeth L.; Kaunitz, Genevieve J.; Cottrell, Tricia R.; Succaria, Farah; McMiller, Tracee L.; Ascierto, Maria Libera; Esandrio, Jessica; Xu, Huimin; Ogurtsova, Aleksandra; Cornish, Toby C.; Lipson, Evan J.; Topalian, Suzanne L.; Engels, Eric A.; Taube, Janis M.

doi:10.1001/jamaoncol.2017.0115

Cited by 67 publications

(50 citation statements)

References 15 publications

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“…PD-L1 expression may be focal and geographic. We have previously validated the use of TMAs for studying PD-L1 expression in squamous cell carcinoma and showed 85% concordance in tumor cell PD-L1 expression between tumor cores and whole-mount sections, 15 but it is possible that requisite sampling ratios may vary by tumor type. Thus the reported rates of PD-L1 expression may be underestimated here in uveal melanomas, where we used TMAs to study a significant proportion of cases.…”

Section: Discussionmentioning

confidence: 99%

“…The TIL intensity grading system has been shown to correlate with TIL counts by digital image analysis in previous studies. 14,15 For the fourteen re-excision specimens that included a primary biopsy site, PD-L1 expression and TIL densities were assessed away from the primary biopsy location. The correlations between PD-L1 expression with CD8+ TIL infiltrates, discrete lymphoid aggregates, and spindle (fusiform) cell morphology were assessed.…”

Section: Methodsmentioning

confidence: 99%

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Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Kaunitz

Cottrell

Lilo

et al. 2017

Laboratory Investigation

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155

112

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PD-L1 expression in the tumor immune microenvironment is recognized as both a prognostic and predictive biomarker in patients with cutaneous melanoma, a finding closely related to its adaptive (IFN-γ-mediated) mechanism of expression. Approximately 35% of cutaneous melanomas express PD-L1, however, the expression patterns, levels, and prevalence in rarer melanoma subtypes are not well described. We performed immunohistochemistry for PD-L1 and CD8 on 200 formalin-fixed paraffin-embedded specimens from patients with acral (n = 16), mucosal (n = 36), uveal (n = 103), and chronic sun-damaged (CSD) (n = 45) melanomas (24 lentigo maligna, 13 ‘mixed’ desmoplastic, and 8 ‘pure’ desmoplastic melanomas). CD8+ tumor-infiltrating lymphocyte (TIL) densities were characterized as mild, moderate, or severe, and their geographic association with PD-L1 expression was evaluated. Discrete lymphoid aggregates, the presence of a spindle cell morphology, and the relationship of these features with PD-L1 expression were assessed. PD-L1 expression was observed in 31% of acral melanomas, 44% of mucosal melanomas, 10% of uveal melanomas, and 62% of CSD melanomas (P<0.0001). Compared to our previously characterized cohort of cutaneous melanomas, the proportion of PD-L1(+) tumors was lower in uveal (P = 0.0002) and higher in CSD (P = 0.0073) melanomas, while PD-L1 expression in the acral and mucosal subtypes was on par. PD-L1 expression in all subtypes correlated with a moderate–severe grade of CD8+ TIL (all, P<0.003), supporting an adaptive mechanism of expression induced during the host antitumor response. The tumor microenvironments observed in CSD melanomas segregated by whether they were the pure desmoplastic subtype, which showed lower levels of PD-L1 expression when compared to other CSD melanomas (P = 0.047). The presence of lymphoid aggregates was not associated with the level of PD-L1 expression, while PD-L1(+) cases with spindle cell morphology demonstrated higher levels of PD-L1 than those with a nested phenotype (P<0.0001). Our findings may underpin the reported clinical response rates for anti-PD-1 monotherapy, which vary by subtype.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Kaunitz

Cottrell

Lilo

et al. 2017

Laboratory Investigation

Self Cite

155

112

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“…124,125 More specifically, the early studies were performed in patients with muscle invasive carcinoma; however, trials are currently underway for non-muscle-invasive disease (NCT02451423, NCT02625961). When tumor cell and immune cell PD-L1 expression were evaluated as potential biomarkers of response to therapy in this tumor type, investigators found that immune cell PDL1 expression is more predictive of response to PD1/ PD-L1 signaling inhibition than tumor cell PD-L1 expression.125 This may be because there is a component of constitutive PD-L1 expression by tumor cells, as has been reported in tumors arising from squamous-type epithelium 12,126 (Figure 2b). 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.…”

Section: Urothelial Carcinomamentioning

confidence: 93%

“…A combined (constitutive plus adaptive) pattern of PD-L1 expression may also be seen in some tumors. 12,21 …”

Section: Immune Checkpointsmentioning

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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“…Staining for PD-L1 (15) and PD-1 (16) was performed as previously described. Immunohistochemistry (IHC) staining for LAG3, CD8, and CD163 were performed according to standardized institutional protocols.…”

Section: Methodsmentioning

confidence: 99%

Characterization of the Immune Microenvironment in Hepatocellular Carcinoma

Yarchoan

Xing

Luan

et al. 2017

Clinical Cancer Research

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123

102

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Purpose Hepatocellular carcinoma (HCC) often arises in the setting of chronic liver inflammation and may be responsive to novel immunotherapies. Experimental Design To characterize the immune microenvironment in HCC, IHC staining was performed for CD8-positive T lymphocytes, PD-1–positive, and LAG-3–positive lymphocytes, CD163-positive macrophages, and PD-L1 expression in tumor and liver background from 29 cases of resected HCC. Results Expression of CD8 was reduced in tumor, and expression of CD163 was reduced at the tumor interface. Positive clusters of PD-L1 expression were identified in 24 of 29 cases (83%), and positive expression of LAG-3 on tumor-infiltrating lymphocytes was identified in 19 of 29 cases (65%). The expression of both PD-L1 and LAG-3 was increased in tumor relative to liver background. No association between viral status or other clinicopathologic features and expression of any of the IHC markers investigated was noted. Conclusions LAG-3 and PD-L1, two inhibitory molecules implicated in CD8 T-cell tolerance, are increased in most HCC tumors, providing a basis for investigating combinatorial checkpoint blockade with a LAG-3 and PD-L1 inhibitor in HCC.

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Association of HIV Status With Local Immune Response to Anal Squamous Cell Carcinoma

Cited by 67 publications

References 15 publications

Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Melanoma subtypes demonstrate distinct PD-L1 expression profiles

Implications of the tumor immune microenvironment for staging and therapeutics

Characterization of the Immune Microenvironment in Hepatocellular Carcinoma

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