Modeling Neoantigen and TCR Dynamics in Melanoma and Its Role in Acquired Resistance to Immunotherapy Using Autologous Thymus-Bearing Humanized Mice
Abstract
This proposal focuses in melanoma. Our project addresses the fact that military personnel suffer from higher rates of melanoma due to increased sun exposure in high-ultraviolet (UV) areas or by flying at high altitude. It also addresses unmet gaps in the treatment of melanoma such as resistance to anti-melanoma drugs that affect the general population but that have a particularly profound impact on active duty Service members, Veterans, and their beneficiaries. In order to become a malignant melanoma cell, the pre-cancerous cell needs to evade the immune system, which they do by hijacking the expression of proteins that are usually expressed by normal cells to signal that they are friendly. However, the “Achilles’ heel” of cancer cells is that the genetic mutations they carry lead to the expression of foreign proteins (neoantigens) that make it easier for the immune system to identify them as foes. It is this delicate balance that the advent of immune-directed therapies has exploited. Immune-directed drugs either activate immune cells to be more vigilant or remove the friendly signals so cancer cells are seen for what they are, foreign entities that need to be eliminated. However, cancers adapt their profiles and evade both natural detection and destruction by the immune system, as well as the therapies that have been developed by selecting clones within their ranks that have mutations that generate a more friendly profile. Essentially, this selection changes the neoantigen profile so that the existing set of immune cells cannot detect and eliminate them. Thus, immune-directed therapies have opened up a new horizon of opportunity, but also a new set of challenges. A key difficulty has been that previous animal models of cancer depend on wiping out a rodent’s immune system so that it won’t attack tumor cells it sees as foreign. But without an immune system, the models can’t teach us how cancer evades immune surveillance nor can they test immunotherapies, whose actions depend on the presence of an immune system. The solution we proposed and initiated in 2010 with a Peer Reviewed Cancer Research Program (PRCRP) New Investigator Award was to transplant a human immune system along with human tumor samples to create humanized animal models. These models with both cancer and an intact immune system allow us to test the ability of new drugs and treatments to turn the immune system against cancer. Our system has evolved considerably since then and incorporates improvements that make its reproduction of the immune system in mice more faithful. These include the use of thymic tissue, which allows immune cells to be properly educated. We can now monitor the neoantigen profiles in tumors, and in this proposal we plan to do so while the tumors receive therapy to test which variations indicate a change in drug susceptibility. We will also monitor the immune response to generate effector T cells by sequencing their profiles. We plan to (1) use existing tumor tissue, blood cells, and humanized mouse models from melanoma patients in up to 10 cases, (2) generate their neoantigen profiles and monitor their response to therapy, and (3) identify which profiles are associated to resistance (either from the start or acquired after an initial response). The overarching goal is to identify the mechanisms responsible for the tumors to change their appearance and becoming resistant to existing therapies. This is a project with a high potential impact that is essentially de-risked given that both the clinical trial and the animal models are already supported by Federal funding, and we will leverage those existing resources to focus on exploring an entirely new and unsupported avenue. We will achieve our goals by taking advantage of a unique set of circumstances. First, a cutting-edge team of cancer biologists, immunologists, and stem cell biologists able to generate humanized patient tumor models, enabled by a past PRCRP aw
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810385
Entities
People
- Antonio Jimeno
Organizations
- United States Army
- University of Colorado Denver