Chronic Lymphocytic Thyroiditis May Modulate Tumor Microenvironment and Elicit Antitumor Immune Response Influencing Clinical and Pathological Features of Differentiated Thyroid Carcinomas

OBJECTIVE: RET proto-oncogene rearrangements (ret/PTCs) represent the most common genetic alterations found in papillary thyroid carcinomas (PTCs). Correlation of ret/PTC expression with clinical outcome is controversial. The aim of the present study was to analyze the frequency of RET rearrangements in adult PTCs, and to investigate if ret/PTCs influence biological behavior and clinical features of the cancers. DESIGN: Ret/PTC rearrangements were looked for in tIssue samples of 48 PTCs collected at our institution. Data about clinical and pathological features of the tumors were also reviewed. Three separate association analyses were carried out on the cohort evaluating the effects of, respectively, ret/PTC positivity, preferential RET tyrosine kinase domain (RET-TK) expression, and ret/PTC plus RET-TK positivity, on age, sex, tumor size, staging, number of neoplastic foci, and histological subtype. METHODS: The genetic study was conducted with the RT-PCR-Southern blot technique. Standard Student's t-test and Fisher exact test were applied for the association analyses. RESULTS: The molecular genetic study demonstrated the positivity of ret/PTC1 and ret/PTC3 in 13 of 48 tumors (27.1%), and an exclusive or preferential RET-TK expression in 17 cases (35.4%). None of the three genetico-clinical analyses showed any significant association between ret/PTC expression and the clinical and pathological features of the cancers. CONCLUSIONS: These data indicate that RET rearrangements may not play any distinctive role in driving histotype development and cancer progression in these neoplasms. Moreover, they weaken the possibility of using ret/PTC as a prognostic marker for papillary thyroid carcinomas.

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CD155/CD96 promotes immunosuppression in lung adenocarcinoma (LUAD)

10.1101/688812 ◽

2019 ◽

Author(s):

Weiling He ◽

Hui Zhang ◽

Shuhua Li ◽

Yongmei Cui ◽

Ying Zhu ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Tumor Microenvironment ◽

Lung Adenocarcinoma ◽

Cd8 T Cells ◽

Immune Suppression ◽

Sodium Dodecyl ◽

Antitumor Immune Response ◽

Patient Derived Xenograft ◽

Poliovirus Receptor

AbstractLung adenocarcinoma (LUAD) remains one of the leading causes of death in patients with cancer. The association of CD155 with CD96 transmits an inhibitory signal and suppresses antitumor immune response. This study investigates the effect of CD155/CD96 on immune suppression in LUAD. We demonstrate that LUAD patients with high CD155 expression suffer from immune suppression and experience a poor prognosis, which coincides with an inhibited AKT-mTOR signaling pathway in CD8 T cells and subsequently up-regulated CD96 expression. Moreover, the inhibition effect can be reversed by CD96 blocking antibody. High CD155 expression inhibited the release of IFNγ from CD8 cells. Moreover, Blocking CD96 restored IFNγ production in CD8 T cells and neutralized the inhibition of IFNγ production in CD8 T cells mediated by CD155. Animal experiments showed that CD155-mediated LUAD growth might depend on its suppression antitumor immune response in the tumor microenvironment in PDX mice. In conclusion, our results suggest that LUAD cells suppress antitumor immune response in the tumor microenvironment through CD155/CD96. CD155/CD96 could be a potential therapeutic target for LUAD patients.AbbreviationsLUAD: lung adenocarcinoma; IFNγ: interferon gamma; PDX: patient-derived xenograft; NSCLC: non-small cell lung cancer; PRR: poliovirus receptor–related; MDSCs: myeloid-derived suppressor cells; PRR: poliovirus receptor–related; STR: short tandem repeat; IRS: immunoreactive score; SI: staining intensity; PP: percentage of positive cells; RT-PCR: reverse transcription-polymerase chain reaction; PBS: phosphate-buffered saline; PBMCs: peripheral blood mononuclear cells; SDS–PAGE: sodium dodecyl sulfate-polyacrylamide gel electrophoresis; rCD155: recombinant human CD155; LUAD cells: lung adenocarcinoma cells; TILs: tumor-infiltrating lymphocytes; GzmB: granzyme B; IL-2 (Interleukin-2); TNF-α : tumor necrosis factor-alpha; PI: propidium Iodide; PDX: patient-derived xenograft; TIGIT: T cell immunoreceptor with Igand ITIM domains; WBC: white blood cells; MFI: mean fluorescence intensity; HPF: high power field

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The Immune Response of Children with Chronic Lymphocytic Thyroiditis to a Viral Challenge

PEDIATRICS ◽

10.1542/peds.37.6.1009 ◽

1966 ◽

Vol 37 (6) ◽

pp. 1009-1011

Author(s):

Allen W. Root ◽

Alfred M. Bongiovanni ◽

Wanlter R. Eberlein

Keyword(s):

Immune Response ◽

Adenovirus Type ◽

Control Group ◽

Chronic Lymphocytic Thyroiditis ◽

Viral Challenge ◽

Lymphocytic Thyroiditis ◽

Control Subjects ◽

Antibody Titers ◽

The Mean ◽

Adenovirus Vaccine

Twenty-eight children with CLT and 22 control subjects were immunized with an adenovirus vaccine. The mean anti-Adenovirus Type 7 titer after vaccination in the group with CLT was significantly less than that in the control group. No significant changes occurred in anti-thyrold antibody titers consequent to the immunization. Patients with CLT had higher mean anti-A and anti-B titers than did control subjects. It is concluded that patients with CLT do not hyperrespond to a viral challenge.

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Abstract A02: Imprime PGG modulates the myeloid component of the tumor microenvironment to coordinate an antitumor immune response

10.1158/1538-7445.fbcr15-a02 ◽

2016 ◽

Cited By ~ 3

Author(s):

Kathryn Fraser ◽

Nadine Ottoson ◽

Xiaohong Qiu ◽

Anissa SH Chan ◽

Adria Jonas ◽

...

Keyword(s):

Immune Response ◽

Tumor Microenvironment ◽

Antitumor Immune Response

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Re-educating the Tumor Microenvironment in the Clinic

Blood ◽

10.1182/blood.v126.23.sci-48.sci-48 ◽

2015 ◽

Vol 126 (23) ◽

pp. SCI-48-SCI-48

Author(s):

Stephen Ansell

Keyword(s):

Immune Response ◽

T Cell ◽

Tumor Microenvironment ◽

Hodgkin Lymphoma ◽

Research Funding ◽

T Regulatory Cells ◽

Suppressor Cells ◽

Immune Checkpoint Blockade ◽

Antitumor Immune Response ◽

Non Hodgkin Lymphoma

The tumor microenvironment plays a central role in lymphoproliferative disorders and constitution of the microenvironment is associated with patient outcome. Although malignant lymphocytes predominate, cells other than tumor cells are commonly present in malignant lymph nodes. These cells include T lymphocytes, NK cells, dendritic cells and monocytes that seem to be more than simple residual elements from the normal lymph node structure. It is thought that these infiltrating immune cells are part of an antitumor immune response, yet they appear unable to eradicate the malignant clone. Previous studies have shown however that multiple factors present in the tumor microenvironment oppose an effective antitumor immune response. Cells with suppressive function, including T regulatory cells, myeloid derived suppressor cells and suppressive monocytes, are abundant in lymphoma tissue. Suppressive cytokines such as TGFβ and IL-10 are highly expressed in tumors. Furthermore, intratumoral T-cell exhibit an exhausted phenotype with limited proliferation, cytokine production or cytolytic function. Recent therapeutic approaches have focused on overcoming T-cell suppression by activating T-cells or blocking inhibitory signals, thereby re-educating the suppressive tumor microenvironment. Clinical trial results with PD-1 and CTLA-4 directed antibodies in both non-Hodgkin lymphoma and Hodgkin lymphoma have been very promising. Overall response rates particularly in Hodgkin lymphoma patients treated with anti-PD-1 antibodies have been remarkable, although complete responses have been uncommon. Current studies are in progress to confirm the initial results, and further trials will assess the efficacy of immune checkpoint blockade in combination with standard therapies. Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding.

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Tumor Microenvironment Immune Response in Pancreatic Ductal Adenocarcinoma Patients Treated With Neoadjuvant Therapy

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djaa073 ◽

2020 ◽

Cited By ~ 1

Author(s):

Theodoros Michelakos ◽

Lei Cai ◽

Vincenzo Villani ◽

Francesco Sabbatino ◽

Filippos Kontos ◽

...

Keyword(s):

Immune Response ◽

Tumor Microenvironment ◽

Pancreatic Ductal Adenocarcinoma ◽

Neoadjuvant Therapy ◽

Cell Density ◽

Antitumor Immune Response ◽

Ductal Adenocarcinoma ◽

M2 Macrophage ◽

Macrophage Density ◽

Cd8 Cell

Abstract Background Neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and chemoradiation have been used to downstage borderline and locally advanced pancreatic ductal adenocarcinoma (PDAC). Whether neoadjuvant therapy-induced tumor immune response contributes to the improved survival is unknown. Therefore, we evaluated whether neoadjuvant therapy induces an immune response towards PDAC. Methods Clinicopathological variables were collected for surgically resected PDACs at the Massachusetts General Hospital (1998-2016). Neoadjuvant regimens included FOLFIRINOX with or without chemoradiation, proton chemoradiation (25 Gy), photon chemoradiation (50.4 Gy), or no neoadjuvant therapy. Human leukocyte antigen (HLA) class I and II expression and immune cell infiltration (CD4+, FoxP3+, CD8+, granzyme B+ cells, and M2 macrophages) were analyzed immunohistochemically and correlated with clinicopathologic variables. The antitumor immune response was compared among neoadjuvant therapy regimens. All statistical tests were 2-sided. Results Two hundred forty-eight PDAC patients were included. The median age was 64 years and 50.0% were female. HLA-A defects were less frequent in the FOLFIRINOX cohort (P = .006). HLA class II expression was lowest in photon and highest in proton patients (P = .02). The FOLFIRINOX cohort exhibited the densest CD8+ cell infiltration (P < .001). FOLFIRINOX and proton patients had the highest CD4+ and lowest T regulatory (FoxP3+) cell density, respectively. M2 macrophage density was statistically significantly higher in the treatment-naïve group (P < .001) in which dense M2 macrophage infiltration was an independent predictor of poor overall survival. Conclusions Neoadjuvant FOLFIRINOX with or without chemoradiation may induce immunologically relevant changes in the tumor microenvironment. It may reduce HLA-A defects, increase CD8+ cell density, and decrease T regulatory cell and M2 macrophage density. Therefore, neoadjuvant FOLFIRINOX therapy may benefit from combinations with checkpoint inhibitors, which can enhance patients’ antitumor immune response.

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