Dissertation
Targeting the Toll/interleukin-1 receptor family as an immunotherapeutic strategy for head and neck squamous cell carcinoma
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2024
DOI: 10.25820/etd.007681
Abstract
The majority of head and neck squamous cell carcinoma (HNSCC) patients are diagnosed with advanced locoregional disease (stage III or IVA/B). Despite achieving local control with radiotherapy (RT), these patients remain at high risk for developing recurrent and/or metastatic (R/M) tumors. Immunotherapy with antibodies targeting programmed cell death protein-1 (PD-1) have shown great promise and have been approved as first-line treatment for R/M HNSCC. However, only a small fraction of patients respond to these therapies, highlighting the urgent need for improved therapies for HNSCC.
HNSCCs are characterized by an immunosuppressive tumor microenvironment which include the impairment of the maturation and function of dendritic cells (DCs). DCs are pivotal in orchestrating the immune system's anti-tumor response by initiating both innate and adaptive immunity. Consequently, strategies that enhance DC activation and function could potentially boost anti-tumor immunity in HNSCC. These studies aim to investigate novel therapeutic approaches for DC activation using the cytokine interleukin-1 alpha (IL-1α) and agonists to endosomal toll-like receptors (TLRs).
Our initial strategy described in Chapter 2, consisted of the encapsulation of recombinant IL-1α (rIL-1α) within different polymeric microparticles (MPs) to screen for release kinetics. The IL-1α-MPs were characterized by size, charge, loading efficiency, and in vitro release and activity. These IL-1α-MPs were injected intraperitoneally (i.p.) into HNSCC-bearing C57Bl/6 mice and monitored for toxicity and anti-tumor efficacy. Results showed that only the CPH:SA_IL-1α-MPs demonstrated the desired slow and sustained release kinetics of rIL-1α, which resulted in minimal toxicity compared to unencapsulated rIL-1α and other control and IL-1α-MPs. Moreover, CPH:SA_IL-1α-MPs showed similar delays in tumor growth and increases in tumor-infiltrating immune cells (i.e. DCs, CD3+ T cells, and macrophages) compared to unencapsulated rIL-1α suggesting that CPH:SA_IL-1α-MPs may represent a safe and promising immunotherapeutic strategy to increase DC infiltration to the tumor microenvironment and boost anti-tumor response.
In Chapter 3, we used the above-described CPH:SA_IL-1αMPs to study if rIL-1α will enhance the anti-tumor efficacy of RT. In vivo, tumor response to RT (to one tumor only) with and without i.p. delivery of CPH:SA_IL-1αMPs was conducted in C57BL/6 mice bearing bilateral flank HNSCC tumors. We found that the combination of RT + CPH:SA_IL-1α-MPs significantly slowed down both RT and non-RT tumor growth compared to control which was accompanied by significantly increased infiltration of DCs in the RT tumors, and increased CD8+ and tumor-specific CD8+ T cell infiltration in both RT and non-RT tumors. These data suggest that the addition of CPH:SA_IL-1αMPs to RT may boost anti-tumor immune response, target both local and systemic disease, and represent a promising approach to lower the risk of locoregional recurrences after RT.
In Chapter 4, we focused on DC activation using virus-like particles (VLPs) encapsulating agonists to endosomal TLRs (i.e. TLR7, TLR7/8, and TLR9). Human PBMCs were used to study the immune-activating properties of each VLP. Results showed that all the tested VLPs activated DCs, however the TLR7/8 agonist in particular activated DCs in addition to T cells and NK cells to a greater extent compared to other VLPs. We also found that TLR7/8a VLP-mediated activation of T cells was highly dependent on direct contact with DCs. These results suggest that TLR7/8 VLPs may induce a robust anti-tumor immune response and is worthy of further investigation as a novel immunotherapeutic strategy.
Finally, in Chapter 5, we summarized key findings and proposed future studies to establish particle delivery of IL-1α and TLR 7/8 agonists as potential immunotherapies for HNSCC. Our study highlights the importance of DC activity in anti-tumor immune responses and that the delivery of IL-1α and agonists to endosomal TLRs using polymeric particles and VLPs respectively can activate DCs and boost anti-tumor immune responses. The incorporation of these agents into existing immunotherapeutic protocols for HNSCC would represent a significant advancement in therapy options for locally advanced and R/M HNSCC patients.
Details
- Title: Subtitle
- Targeting the Toll/interleukin-1 receptor family as an immunotherapeutic strategy for head and neck squamous cell carcinoma
- Creators
- M M Hasibuzzaman
- Contributors
- Andrean L. Simons-Burnett (Advisor)Aliasger K. Salem (Committee Member)Gabriele Ludewig (Committee Member)George J. Weiner (Committee Member)Joseph M. Caster (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Summer 2024
- DOI
- 10.25820/etd.007681
- Publisher
- University of Iowa
- Number of pages
- xii, 152 pages
- Copyright
- Copyright 2024 M M Hasibuzzaman
- Language
- English
- Date submitted
- 07/22/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 134-152).
- Public Abstract (ETD)
Head and neck squamous cell carcinomas (HNSCCs) are deadly cancers, and people who diagnosed at a late stage often have a low chance of survival. The current treatments available for these patients are few and not very effective. Cancer immunotherapy, which aims to boost or reactivate the patient’s immune system to fight the cancer, is a promising approach. However, there are only a few immunotherapy options for these patients, and many do not benefit from the existing treatments.
These studies aim to investigate new immunotherapy treatments to help HNSCC patients live longer. In our research, we have used two immune-modulatory agents: the first is recombinant interleukin-1 alpha (rIL-1α), packed in polymeric micro-sized particles (IL-1αMPs), and the second is endosomal toll-like receptor agonists (TLRa), packed in virus-like particles (TLRa VLPs). We found that delivering rIL-1α slowly through IL-1αMPs is safe and effective. These particles can trigger both local and whole-body immune responses against the tumor. When we combined IL-1αMPs with radiotherapy, we saw that this combination not only helped shrink the main tumor but also reduced the size of tumors located away from the primary treatment site. This suggests that IL-1αMPs can enhance the effectiveness of radiotherapy, especially for advanced cancer.
We also studied and compared the immune-boosting effects of different TLRa VLPs: TLR7a VLP, TLR9a VLP (already being tested in clinical trials), and TLR7/8a VLP. We discovered that TLR7/8a VLP is particularly good at activating various types of immune cells, leading to better activation of T cells and natural killer (NK) cells. These promising immune-boosting properties of TLRa VLPs could make them useful either alone or combined with other treatments.
Overall, our results indicate that both IL-1αMPs and TLRa VLPs show great promise and should be further studied to help improve the survival rates of HNSCC patients.
- Academic Unit
- Interdisciplinary Studies Program
- Record Identifier
- 9984698053102771
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