Research: The discovery of immune checkpoint blockade (ICB) therapies has sparked a revolution in the clinical approach to cancer treatment, however the efficacy of these therapies has varied across different cancer types. In particular, pancreatic adenocarcinoma (PDA) represents a particularly resilient and lethal form of malignancy, with an average survival time of 3-3.5 years following initial diagnosis. This is due to a dense stromal network and high expression of immune suppressive factors, which are believed to promote T cell exhaustion and limit T cell infiltration into the tumor. ICB is believed to operate by inducing differentiation of effector T cells from a progenitor memory/stem-like CD8 T cell subset, which appear resistant to exhaustion. It is unknown if low or high affinity tumor-reactive T cells are being unleashed by ICB and how TCR affinity impacts T cell fate decisions. It is also unknown where these stem-like T cells reside in pancreatic cancer and factors that contribute to their maintenance and function. This knowledge would help inform TCR selection for cell therapy for PDA patient treatment.
During my thesis, I have characterized a total of 4 recently cloned T cell receptors (TCRs) specific to a model neoantigen, click beetle red (CB) luciferase, that differ in tetramer binding and 2D affinity. I have characterized the functionality of these TCRs, and generated T cell receptor exchange mice (TRex) which serve as a reproducible source of tumor-specific T cells for a tractable, antigen-specific T cell population. These TRex T cells have been demonstrated to hone to CB+ KPC tumors, where they form anti-tumor effectors. Notably, the lowest affinity TCR clonotype appears to be selectively maintained in a progenitor exhausted phenotype by the addition of ICB therapy, and is enriched in all treatment conditions by day 21 compared to other transferred TRex populations. I will continues to assess the interactions between various antigen presenting cells and T cells over time and during immunotherapy, as well as utilize these TRex T cells to identify localization of progenitor and exhausted T cells in vivo (dLN, spleen, tumor) using spatial analysis. Thus, I will determine the consequence of tumor antigen presentation by myeloid cells to tumor-reactive T cells with varying TCR binding affinities on T cell fate and functionality. With this in mind, I hope to be able to improve T cell cytotoxicity and longevity through engineered TCR cell therapy and modulation of the tumor myeloid compartment.
