Engineering tissue-resident lymphocytes for the modulation of tissue-microenvironments
Local networks of tissue-resident lymphocytes are strategically positioned in most anatomical compartments and barrier surfaces, where they participate in front-line defense to microbial invasion and tumor immune surveillance. Tissue-resident memory T cells (TRM) can seed, persist and function in distinct tissue-niches, including epithelial compartments. A large fraction of human tumors emanates from epithelia and TRMs have been found to be critical for intraepithelial tumor immune-surveillance. TRM cells act as sentinels that can modulate the tissue-state, immune responses of bystander lymphocytes and facilitate the recruitment of additional cell types. Therefore, TRMs represent promising targets for cellular therapies aiming at the modulation of local microenvironments but strategies to exploit this potential remain largely unexplored to date.
Based on findings in the field of TRM cell biology, we propose to engineer cells that can (1) home to, (2) function in and (3) modulate specific tissue-environments. To this end, we will establish culture conditions that allow us to generate “TRM-like” cells for adoptive cell therapy, taking advantage of a novel reporter mouse line for the transcription factor Hobit which drives transcriptional programs of tissue-residency (Aim1). We will complement these approaches by engineering molecules that can optimize tissue homing and recruitment of adoptively transferred T cells. The ability of engineered T cells to become TRM-like cells in vivo will be validated in response to viral infection and in tumor models.
In Aim 2, we will systematically interrogate and validate TRM-specific genes for their suitability to engineer TRM-like cells for adoptive cell therapy using CRISPR/Cas9-mediated screening as well as targeted engineering of T cells. To validate the potential for translation into future therapeutic approaches, identified targets will be tested through sgRNP mediated KO and retroviral overexpression in primary human T cells for their ability to modulate TRM-like T cell differentiation.
In parallel (Aim 3), we will explore the potential of engineering type 2 innate lymphoid cells (ILC2) that are now being recognized for their ability to seed tumors and to modulate the microenvironment and anti-tumor immunity. We will explore the ability of “armed” ILC2s to modulate local environments through the delivery of engineered cytokines. In summary, we will exploit the biology of tissue-resident lymphocytes to advance the engi- neering of cells with improved tissue-homing and functionality, which represent a major bottleneck of current cellular therapies.
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