Ruffin, Ayana
(2022)
Evaluating B cell phenotype and function in the tumor microenvironment of head and neck cancer.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
B lymphocytes (B cells) are crucial for producing antibodies that provide lifelong protection against invading pathogens. Prevalence of B cells in human solid tumors correlates with favorable outcomes and can predict response to current immune checkpoint inhibitors (ICI). However, their role in immune responses to solid tumors remains understudied. To determine the therapeutic potential of B cells, it is critical to characterize B cell phenotype and function within different tumor microenvironments (TMEs).
Patients with HNSCC caused by human papilloma virus (HPV+) have significantly higher germinal center like (GC-like) B cells and tertiary lymphoid structures (TLS) in their tumors compared to carcinogen driven HNSCC tumors (HPV-)which correlated with better overall survival. Patients had superior outcomes in both etiologies when their TLS contained GCs. Semaphorin4a (Sema4a) marks GC-like B cells and its expression increases as naïve B cells differentiate into GC-like B cells in HNSCC (Chapter 3). Class-switched (SW; CD27+) memory B cells (MBC), which can be products of GCs are increased in both HPV+ and HPV- HNSCC tumors and peripheral blood (PBL) compared to inflamed tonsil and healthy donor PBL. I also report an increase in a two extrafollicular, or GC independent B cell subpopulations termed double negative 2 (DN2) (CD11c+CD27- IgD- CD21-) and double negative 3 (DN3) (CD11c-CD27- IgD- CD21-) in HNSCC patients.DN3 B cells are increased in locally advanced (LA) HNSCC tumors with higher tumor stage and more prevalent in HPV- patients but DN2s are absent in HNSCC tumors. DN3 are also abundant in PBL of patients with metastatic melanoma (MEL) and lung cancer while DN2s were abundant in HNSCC and Lung cancer PBL. Higher frequency of circulating DN3 was observed in MEL patients with progressive disease. Lastly, I show that DN3 and DN2 B cells are less functional than SW MBC (Chapter 4).
Taken together, my findings suggest that the presence of GC B cells and TLS formation in the TME may be indicative of having an enhanced anti-tumor response mediated by T cells and overall better control of disease. Accumulation of intratumoral and circulating DN3 B cells may be indicative of an immunosuppressive microenvironment.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
14 November 2022 |
| Date Type: |
Publication |
| Defense Date: |
26 July 2022 |
| Approval Date: |
14 November 2022 |
| Submission Date: |
5 August 2022 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
242 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
B cells, Head and Neck cancer, immunotherapy, |
| Date Deposited: |
14 Nov 2022 17:45 |
| Last Modified: |
14 Nov 2022 17:45 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/43526 |
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