Cancer immunotherapy has gained attention in recent years for its successes in potentiating immune responses that can elicit tumor control. In particular, adoptive cell therapy (ACT), which involves the autologous/allogeneic transplant of ex vivo-cultivated tumor-specific T lymphocytes, can mediate potent tumor recognition and killing; however, durable clinical responses are often difficult to obtain in solid tumors. Solid tumors and their unique microenvironments have the capacity to evade and suppress antitumor immune responses and represent significant hurdles for effective ACT. Recently, we have discovered that chemical inhibition of histone deacetylases via MS-275 (Entinostat) during ACT can subvert tumor resistance to foster potent, broad-spectrum antitumor immunity. Overall, the work described supports the efficacy of ACT in the treatment of immunosuppressive, solid tumors; however, consistency in durable clinical outcomes can only be achieved through the concurrent therapeutic targeting of tumor resistance mechanisms.
This thesis uses pre-clinical models to describe how tumor resistance to ACT can manifest, and demonstrates that concurrent MS-275 delivery drives extensive immunomodulation to promote sustained tumor clearance. This includes:
1) The polarization of tumor-infiltrating myeloid cells into cytotoxic effectors with the ability to reject immune escape variants
2) The inflammatory remodeling of the tumor microenvironment to potentiate epitope spreading against secondary tumor antigens
3) The transcriptional reprogramming of adoptively transferred T cells to overcome tumor-burden-dependent exhaustion
We expect that the results will help facilitate the development of next-generation ACT platforms that will feature strategies for multi-mechanistic perturbation of tumor resistance. / Thesis / Doctor of Philosophy (PhD) / The host immune system has the ability to recognize and destroy tumor cells. Therapeutic platforms that leverage antitumor immune cells, specifically T cells, have shown potency in the elimination of cancer. In the clinic, cancer immunotherapies have demonstrated early success against hematological malignancies; however, are unreliable in the treatment of solid tumors. Solid tumors utilize intrinsic and adapted mechanisms of resistance to mitigate the effectiveness of cancer immunotherapy. This thesis pursues research questions aimed at understanding how tumors resist immunotherapy, what mechanisms are utilized, and how to overcome these obstacles. We anticipate that these results will contribute to the development and incorporation of strategies to subvert tumor resistance and potentiate T cells against solid tumors.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27355 |
| Date | 20 December 2021 |
| Creators | Nguyen, Andrew |
| Contributors | Wan, Yonghong, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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