Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor T cell transfer are showing promising results both in trials and in clinical ...practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however, the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response and can be targeted through the use of antiangiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells, controlling the microenvironment, and modulating the immune response. Improving access to the tumor through vascular alteration with antiangiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches and might be applicable to many tumor types. In this review, we briefly discuss the host's immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.
Four different programmed death ligand 1 immunohistochemical assays are approved or in development as companion or complementary diagnostics to different immunotherapeutic agents in lung carcinoma. ...We sought to determine whether these assays are technically equivalent and whether one antibody can be used on an alternate staining platform.
Serial sections of tissue microarrays constructed from 368 cases of resected lung cancer were stained for 22C3 and 28-8 on the Dako Link 48 platform (Dako, Carpinteria, Ca) and for SP142 and SP263 on the Ventana Benchmark Ultra platform (Ventana Medical Systems, Tucson, AZ) strictly as per product insert. A protocol was developed to use the 22C3 antibody on the Ventana Benchmark Ultra platform.
Differences in mean tumor cell and immune cell staining were observed between the four assays (p < 0.001). Differences between 22C3 and 28-8 were not statistically significant. Concordance of tumor cell scores was good (intraclass correlation coefficient ICC = 0.674), particularly when SP142 was excluded as an outlier (ICC = 0.755). The highest concordance was seen between 22C3 and 28-8 (ICC = 0.812). Concordance was poor for immune cell staining (ICC = 0.212). When dichotomized according to clinically relevant cutoffs, pairwise comparisons showed poor to moderate concordance (κ = 0.196–0.578), with positive percent agreement ranging from 15.1% to 90.0%. The 22C3 antibody performed comparably on the Dako Link 48 platform and the alternate Ventana Benchmark Ultra platform (ICC = 0.921, κ = 0.897).
Concordance between the four programmed death ligand 1 immunohistochemical assays when performed and scored as intended show that apart from 28-8 and 22C3, they cannot be used interchangeably in clinical practice. A protocol was successfully developed to use 22C3 on an alternate platform, which may help to overcome some barriers to implementation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The immune microenvironment of breast ductal carcinoma
(DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.
We quantified tumor associated ...lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (
= 55) and mutation data (
= 20).
TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%-90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (
= 0.002/0.035), ER-negative (
= 0.02/0.02), and
-amplified tumors (
< 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (
< 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with
mutation (
= 0.03) but not with
or
mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both
< 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.
Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor.
.
Human papilloma virus-positive oropharyngeal squamous cell carcinoma (HPV
OPSCC) represents a distinct subgroup of head and neck cancers associated with clinical outcomes that are not accurately ...categorized by existing tumor-node-metastasis-based staging methods. Given the significant impact of immune parameters, such as tumor-infiltrating lymphocytes (TIL) in many cancers, we sought to determine if immunophenotyping tumors can improve categorization of HPV
OPSCCs for prognostic purposes. In a cohort of 190 patients with HPV
OPSCC, we quantified and determined the localization of CD8
TILs, as well as PD-L1-expressing tumor cells (TC) and immune cells (IC). The prognostic significance of these parameters on overall survival (OS) was evaluated, and their contribution to existing prognostic models was determined. High CD8
TIL abundance (≥30% on stromal or intratumoral ICs) was seen in 61.3% patients and was associated with improved OS HR, 0.4; 95% confidence interval (CI), 0.2-0.9;
= 0.017. Although the expression of PD-L1 on TC was not prognostic, high expression of PD-L1 on ≥5% of intratumoral ICs was found in 38.5% patients and was significantly associated with improved OS (HR, 0.37; 95% CI, 0.15-0.93;
= 0. 023). Both high intratumoral IC PD-L1 expression and abundant CD8
TILs in HPV
OPSCCs identify subgroups of patients with excellent outcomes and provide additional prognostic information beyond existing staging systems.
.
Background
The role of 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the ...correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS).
Methods
Patients with the above histological subtypes in three participating institutions with preoperative 18F‐FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse‐free survival (RFS) and overall survival (OS) were also studied.
Results
Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2–33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (rs = 0.40, p = .002). Increasing SUVmax was associated with worse RFS (p = .003) and OS (p = .003).
Conclusion
There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Leimyosarcomas arising from the stroma of the prostate are very rare, accounting for 0.1% of malignancies. We describe a case that closely mimicked benign prostatic hypertrophy on magnetic resonance ...imaging. Due to the low incidence of disease there is no high level evidence for management. We advocate neoadjuvant radiotherapy followed by radical prostatectomy with pelvic lymph node dissection. Diagnosis and expedient management is critical.
•Sarcomas of the prostate may mimic benign nodules on MRI.•Sarcomas of the prostate are rare but highly aggressive.•Sarcomas of the prostate should recieve neoadjuvant radiotherapy before radical prostatectomy with bilateral pelvic lymph node dissection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objectives
Tumor‐infiltrating lymphocytes (TIL), particularly CD8+ TILs in patients with colorectal cancer (CRC), are highly prognostic in the early‐disease stages (I‐II). In metastatic disease ...(stage IV; mCRC), their influence is less well defined. It has presumably failed to contain tumor cells to the primary site; however, is this evident? We explored the prognostic impact of TILs at the primary site in patients who presented de novo with mCRC.
Methods
Treatment‐naïve patients (109) with mCRC were assessed for CD8+ TILs and PD‐L1 expression. Microsatellite instability (MSI) was evaluated by IHC for PMS2 and MSH6 proteins and/or by PCR using the Bethesda panel.
Results
Microsatellite instability‐high tumors had significantly more CD8+ TILs, with no significant survival advantage observed between MSI‐H and microsatellite stable (MSS) tumors (12 vs 19 months, P = 0.304). TIL density for all cases had no impact on OS (low: 20 vs high: 13 months, P = 0.426), while PD‐L1 of 1% or higher was associated with reduced mean survival (9.6 vs 18.9 months; P = 0.038). MSI‐H tumors and associated immune cells had higher PD‐L1 expression than in MSS cases. A positive correlation between PD‐L1 on immune cells and CD8+ve TILs was found. A subset of MSS tumors had relatively high TILs approximating that of MSI‐H tumors.
Conclusion
In contrast to early‐stage CRC, the immune response in primary tumors of patients with de novo mCRC does not appear to influence survival. A subgroup of MSS tumors was identified with increased TILs/PD‐L1 comparable to MSI‐H tumors, traditionally not be considered for immune checkpoint blockade and perhaps should be.
Unlike early‐stage colorectal cancer (CRC), the immune response in primary tumors of patients with de novo mCRC does not appear to influence survival despite MSI‐H tumors having higher tumor infiltrating lymphocytes (TILs). This unique cohort of patients with synchronous mCRC by definition represents the breakdown of immune containment of the primary tumor. Despite this, we also identified a subgroup of MSS tumors with a high TILs comparable to MSI‐H tumors and this group traditionally would not be considered for immune checkpoint blockade, and perhaps should be.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
•We describe a new multiplex digital PCR assay that measures PDL1 levels in NSCLC.•The assay is concordant with the FDA approved SP263 immunohistochemistry test.•Our assay/workflow allows for ...additional molecular testing from the same biopsy.•This test is a rapid, cost-effective and reliable assay to identify PDL1 high patients.
Immune checkpoint inhibitors have become integrated into the clinical management of non-small cell lung cancer (NSCLC). Using RTqPCR, we have previously identified a gene expression panel that detected presence of malignant cells (MMP9:TIMP3 ratio) and quantified PD-L1 transcript levels in small biopsy specimens. However, RTqPCR has diagnostic limitations as it does not generate absolute copy number and is not readily multiplexed. To address this, we have developed a multiplex droplet digital PCR (ddPCR) assay.
Biopsies obtained from NSCLC patients (n = 48 adenocarcinoma and n = 40 squamous cell carcinoma) and control lung biopsy specimens (n = 20) were analysed. Absolute MMP9, TIMP3 and PD-L1 transcript copy numbers were determined within a single assay by multiplex ddPCR using Taqman primers and the QX200 Droplet Digital PCR System.
Using our optimised triplex ddPCR assay, the MMP9:TIMP3 ratio was significantly elevated in NSCLC biopsies and using a cut-off of >0.028, was 99% (95% CI; 80.5-94.5) sensitive and 80% specific for identifying malignant biopsies. The PD-L1:TIMP3 ratio significantly associated with PD-L1 tumour cell immunohistochemistry staining (r = 0.539, p < 0.0001) and was significantly higher in biopsies with >50% PD-L1 tumour cell staining (p < 0.0001). In summary, a major advantage of our workflow is that it can accurately quantify PD-L1 tumour levels and provide sufficient nucleic acid for screening additional targetable mutations such as EGFR, ALK and ROS1 from a single small biopsy, thereby potentially avoiding the need for re-biopsy. Future studies will need to determine diagnostic ddPCR values that are predictive of clinical response to PD-1/PD-L1 immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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