Spatial Immunology in Liver Metastases from Colorectal Carcinoma according to the Histologic Growth Pattern
Gemma Garcia‐ViciénArtur MezheyeuskiPatrick MickeNúria RuizJ.C. RuffinelliKristel MilsMaría BañulsN. Martinez MolinaFerrán LosaLaura LladóDavid G. Mollevı́
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Colorectal cancer liver metastases (CRC-LM) present differential histologic growth patterns (HGP) that determine the interaction between immune and tumor cells. We explored the spatial distribution of lymphocytic infiltrates in CRC-LM in the context of the HGP using multispectral digital pathology. We did not find statistically significant differences of immune cell densities in the central regions of desmoplastic (dHGP) and non-desmoplastic (ndHGP) metastases. The spatial evaluation reported that dHGP-metastases displayed higher infiltration by CD8+ and CD20+ cells in peripheral regions as well as CD4+ and CD45RO+ cells in ndHGP-metastases. However, the reactive stroma regions at the invasive margin (IM) of ndHGP-metastases displayed higher density of CD4+, CD20+, and CD45RO+ cells. The antitumor status of the TIL infiltrates measured as CD8/CD4 reported higher values in the IM of encapsulated metastases up to 400 μm towards the tumor center (p < 0.05). Remarkably, the IM of dHGP-metastases was characterized by higher infiltration of CD8+ cells in the epithelial compartment parameter assessed with the ratio CD8epithelial/CD8stromal, suggesting anti-tumoral activity in the encapsulating lesions. Taking together, the amount of CD8+ cells is comparable in the IM of both HGP metastases types. However, in dHGP-metastases some cytotoxic cells reach the tumor nests while remaining retained in the stromal areas in ndHGP-metastases.Keywords:
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Pancreatic ductal adenocarcinomas with high stromal content are shown to have greatly reduced overall survival, consistent with previous reports that stroma may limit drug delivery. In contrast to expectations, metastatic lesions were found to harbor as much stroma as primary tumors.
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CD68
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Pancreatic ductal adenocarcinoma (PDAC) is considered as one of the most aggressive malignancies due to its unique microenvironment of which the cardinal histopathological feature is the remarkable desmoplasia of the stroma, taking up about 80% of the tumor mass. The desmoplastic stroma negatively affects drug diffusion and the infiltration of T cells, leading to an immunosuppressive microenvironment. However, this unique microenvironment can limit the physical spread of pancreatic cancer via a neighbor suppression effect. Here, a tumor central stroma targeting and microenvironment responsive strategy was applied to generate a nanoparticle coloading paclitaxel and phosphorylated gemcitabine. The designed nanoparticle disrupted the central stroma while preserving the external stroma, thereby promoting the antitumor effectiveness of chemotherapeutics. Additionally, the resulting nanoparticle can modulate the tumor immunosuppressive microenvironment by augmenting the number of cytotoxic T cells and restraining the percentage of T regulatory cells. The relatively intact external stroma can effectively maintain the neighbor suppression effect and prevent tumor metastasis. Combining stroma targeting with the delivery of stimuli-responsive polymeric nanoparticles embodies an effective tumor-tailored drug delivery system.
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To investigate peritumoral and intratumoral infiltrates in surgical specimens obtained from patients with invasive breast cancer, and of relating these to tumor size.Twenty-six surgical specimens obtained from patients diagnosed with breast cancer underwent immunohistochemical preparation and CD3, CD8, CD20 and CD68 labeling. The positive cells were counted in the tissue samples and correlated with the tumor size determined by imaging methods (TIA < or = 2 or TIB > 2 cm).There was a significant reduction in intratumoral B lymphocytes (CD20+), although this reduction could only be observed in TIA. In relation to peritumoral T lymphocytes (CD3+), there was a significant reduction in TIB, in comparison with TIA. Peritumoral and intratumoral CD3+ and CD68+ presence in completely opposite ways in both sizes of tumors.Peritumoral and intratumoral infiltrates of T and B lymphocytes are different and depend on tumor size.
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Abstract Objective: The aim of the study was to investigate the localization, amount and type of lymphocytic infiltrate, found in different molecular subtypes of breast cancer (BC). Methods: Retrospectively, 100 cases of invasive BC were analyzed and immunohistochemicaly (IHC) stratified in four subtypes (Luminal A and Luminal B-like, HER2-positive, and triple negative (TN). The percentage of stromal areas occupied by tumor-infiltrating lymphocytes (TILs) was assessed for H&E slides. The samples were IHC-stained for CD3, CD4, CD8, CD20 and FoxP3. The immunophenotyped lymphocytes - intratumoural and stromal, were separately counted, semi-quantitatively graded and further analyzed. Results: A total of 10% of all tumors were lymphocyte-predominant BC. Intratumoral and stromal TILs were predominantly CD3+T-lymphocytes. High counts of all subtypes TILs - intratumoral and stromal, were most common for TNBC and HER2-positive BC. In TNBC, the intratumoral CD3+TILs are significantly related to CD8+ (p=0.002) and FoxP3+ phenotype (p=0.010). In HER2 BC, the intratumoral and stromal CD3+ TILs were significantly related to FoxP3+ phenotype (p = 0,035 and p= 0.011, respectively). Conclusion:CD3+T-cell mediated immunity, especially the one related to CD8+ and FoxP3+ lymphocytes was the leading one in antitumor response in BC, and high count of intratumoral and stromal lymphocytes predominated in TN and HER2-positive BC. Key words: Breast cancer, tumor-infiltrating lymphocytes, CD3, CD4, CD8, CD20, FoxP3. Citation Format: Popovska SL, Dimitrova PD, Dineva TB. A study on amount, localization and immune phenotype of tumor-infiltrating lymphocytes in different subtypes of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-20.
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Objective: To investigate the role of infiltrating lymphocytes in the cutaneous lesions of lichen planus(LP).Methods: The expressions of CD3,CD4,CD8,and CD20 were detected by immunohistochemical SP method in 32 LP patients with cutaneous lesions and 30 normal subjects.Results: In the epidermis,the infiltrating lymphocytes were mainly CD3~+ and CD8~+ T cells and(CD20~+) B cells were found by chance.The predominant cells in the dermis were CD3~+,CD4~+,and CD8+ T cells.With the prolongation of the disease course,the number of infiltrating lymphocytes in the cutaneous lesions reduced(P0.01),the ratio of CD4~+ to CD8~+ T cells in the dermis decreased(P0.05),and the proportion of CD20~+ B cells increased(P0.05).The number of CD20~+ B cells markedly increased in LP patients with hyperplastic changes.Conclusion: CD8~+ T cells are associated with the cutaneous lesions of LP.Imbalance of CD4~+ and CD8~+ T cells exists in the cutaneous lesions.CD20~+ B cells may be related to the continuous immune response and excessively hyperplastic changes in the cutaneous lesions of LP.
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The mechanism of stroma-formation and rearrangement of the stroma was studied on 221 cases of cancer of the lung, stomach and mammary gland using histological, histochemical and electron-microscopy methods of investigation. It was established that multiplying epithelial elements of teh tumour induced proliferation of histiogenic and vascular fibroblasts, activating them. Active fibroblasts play a double role: they either produce fibres and interstitial matter of the tumorous stroma, or participate in desintegration of preceding and newly formed collagenous structures. The processes of stroma-formation comply with the conventional schemes of normal fibrillogenesis and rearrangement of the interstitial tissue. It was shown that fibroblasts of the tumour stroma was capable of phagocytosis of a mature collagen. It is supposed that in the course of the tumorous growth correlation between the parenchyma and stroma is maintained, the leading role being played by the epithelium.
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The swelling properties of the anterior and posterior stroma of bovine and rabbit corneas were examined by three different methods. The results show that the posterior stroma can swell more than the anterior stroma. Also, at a given swelling pressure, the posterior stroma is more hydrated than the anterior stroma. In a third experiment it is demonstrated that the posterior stroma is also more hydrated in the living eye.It is concluded that the stroma is not a homogeneous structure. The superficial stroma has different physiological properties from the deep stroma. These differences must be taken into account in theoretical models of corneal deturgescence.
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Expression of the pan B-cell marker CD20 by T-cell lymphoproliferative disorders is exceedingly rare. We present a 52-year-old man with a unilesional cutaneous CD20+ T-cell lymphoproliferative disorder. Multispectral imaging analysis of CD3–CD20 double-stained lesional tissue sections allowed (1) the visualization of double-positive T lymphocytes in situ with sensitivity superior to that of conventional immunohistochemistry and (2) the quantitative assessment of marker coexpression. Here, 23% of CD3+ signals in the patient's lesion were also CD20+, whereas 38% of CD20 + signals were also CD3+. In contrast, both parameters were below 1% in the tonsil control. Overall, the percentage of double-positive cells in lesional skin was 35%, although only 0.4% of such cells were detected in the tonsil. This is the first demonstration of aberrant CD20 expression by skin-infiltrating T cells using multispectral imaging.
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Lymphoproliferative Disorders
Immunophenotyping
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