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Start Over Author "Timothy N. Bullock" Topic tumor microenvironment
2 results on '"Timothy N. Bullock"'

1. Formation and phenotypic characterization of CD49a, CD49b and CD103 expressing CD8 T cell populations in human metastatic melanoma

Author

Marit M. Melssen, Walter Olson, Nolan A. Wages, Brian J. Capaldo, Ileana S. Mauldin, Adela Mahmutovic, Ciara Hutchison, Cornelis J.M. Melief, Timothy N. Bullock, Victor H. Engelhard, and Craig L. Slingluff

Subjects
integrin, t cells, cd8, cytokines, retention, tumor microenvironment, melanoma, cd103, cd49a, cd49b, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Integrins α1β1 (CD49a), α2β1 (CD49b) and αEβ7 (CD103) mediate retention of lymphocytes in peripheral tissues, and their expression is upregulated on tumor infiltrating lymphocytes (TIL) compared to circulating lymphocytes. Little is known about what induces expression of these retention integrins (RI) nor whether RI define subsets in the tumor microenvironment (TME) with a specific phenotype. Human metastatic melanoma-derived CD8 TIL could be grouped into five subpopulations based on RI expression patterns: RIneg, CD49a+ only, CD49a+CD49b+, CD49a+CD103+, or positive for all three RI. A significantly larger fraction of the CD49a+ only subpopulation expressed multiple effector cytokines, whereas CD49a+CD103+ and CD49a+CD49b+ cells expressed IFNγ only. RIneg and CD49a+CD49b+CD103+ CD8 TIL subsets expressed significantly less effector cytokines overall. Interestingly, however, CD49a+CD49b+CD103+ CD8 expressed lowest CD127, and highest levels of perforin and exhaustion markers PD-1 and Tim3, suggesting selective exhaustion rather than conversion to memory. To gain insight into RI expression induction, normal donor PBMC were cultured with T cell receptor (TCR) stimulation and/or cytokines. TCR stimulation alone induced two RI+ cell populations: CD49a single positive and CD49a+CD49b+ cells. TNFα and IL-2 each were capable of inducing these populations. Addition of TGFβ to TCR stimulation generated two additional populations; CD49a+CD49bnegCD103+ and CD49a+CD49b+CD103+. Taken together, our findings identify opportunities to modulate RI expression in the TME by cytokine therapies and to generate subsets with a specific RI repertoire in the interest of augmenting immune therapies for cancer or for modulating other immune-related diseases such as autoimmune diseases.

Published
2018
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2. MHC class I loss in endometrial carcinoma: a potential resistance mechanism to immune checkpoint inhibition

Author

Lisa A, Friedman, Timothy N, Bullock, Emily A, Sloan, Kari L, Ring, and Anne M, Mills

Subjects
CD3 Complex, Carcinoma, Clinical Decision-Making, Histocompatibility Antigens Class I, DNA Mismatch Repair, Immunohistochemistry, B7-H1 Antigen, Endometrial Neoplasms, Lymphocytes, Tumor-Infiltrating, Drug Resistance, Neoplasm, Predictive Value of Tests, Biomarkers, Tumor, Tumor Microenvironment, Humans, Female, Immune Checkpoint Inhibitors
Abstract

Major histocompatibility complex (MHC) class I is a membrane-bound protein complex expressed on nucleated human cells. MHC class I presents intracellular protein fragments to cytotoxic T cells and triggers an activation cascade upon neoantigen detection by these cells. MHC class I loss by tumor cells decreases tumor neoantigen presentation to the immune system and therefore represents a possible mechanism of immunotherapeutic resistance even among cancers that otherwise appear to be good candidates for checkpoint inhibition, such as mismatch repair (MMR)-deficient and PD-L1-positive malignancies. We herein assess MHC class I expression in a range of endometrial carcinomas, including MMR-deficient and PD-L1-positive cancers. Immunohistochemical staining for combined MHC class I A-, B-, and C-heavy chains was performed on 76 cases of endometrial carcinoma and was classified as present, subclonally lost, or diffusely lost. Tumoral PD-L1 expression, PD-L1 combined positive score, and CD3-positive T lymphocytes were also quantified. Forty-two percent of tumors showed loss of MHC class I expression, either in a subclonal (26%) or diffuse (16%) pattern. This included 46% of MMR-deficient and 25% of PD-L1-positive cancers. These findings suggest that tumoral MHC class I status may be an important factor to consider when selecting endometrial cancer patients for checkpoint inhibition.

Published
2020

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