Periodic Reporting for period 1 - DRILL (Decoding Requirements for Infiltration of T ceLLs into solid tumors)
Período documentado: 2023-01-01 hasta 2025-06-30
Solid tumors often develop dense, fibrous tissue and other hostile conditions that prevent immune cells, especially T lymphocytes, from effectively entering and attacking the cancer. This lack of T cell “infiltration” is widely recognized as a major barrier to immunotherapy success in numerous cancers, including pancreatic cancer. To address this challenge, the DRILL project set out to systematically uncover the molecular factors, both within the tumor microenvironment and inside T cells themselves, that influence how well T cells move into and function within solid tumors. By deciphering these mechanisms, we aim to help design better immunotherapies that enable T cells to reach and destroy tumor cells more efficiently.
This research combines cutting-edge methods in genetics, cell biology, and immunology to identify promising new targets for intervention, whether that is by altering the factors in the tumor microenvironment to draw T cells inward and maintain their functions or engineering T cells to improve their mobility. Ultimately, our goal is to overcome a key limitation in existing immunotherapies and thus improve patient outcomes in immunotherapies. Should these strategies prove successful, their impact could be very significant, potentially transforming the way solid tumors are approached by enabling truly potent T cell responses in cancers.
This research combines cutting-edge methods in genetics, cell biology, and immunology to identify promising new targets for intervention, whether that is by altering the factors in the tumor microenvironment to draw T cells inward and maintain their functions or engineering T cells to improve their mobility. Ultimately, our goal is to overcome a key limitation in existing immunotherapies and thus improve patient outcomes in immunotherapies. Should these strategies prove successful, their impact could be very significant, potentially transforming the way solid tumors are approached by enabling truly potent T cell responses in cancers.
To investigate T cell infiltration from multiple angles, the DRILL project used a broad range of laboratory techniques and experimental models. One key approach involved high-throughput CRISPR/Cas9 “screens” in which thousands of genes in cancer cells and immune cells were individually switched off or switched on (gain of function). These screens were performed under controlled conditions that in vitro mimic the tumor microenvironment or directly in in vivo tumor models.
On the tumor side, we discovered that tumor often regulate their secretion of chemokines (proteins that attract immune cells) in ways that limit T cell entry. In particular, we found high levels of a transcription factor strongly upregulated in certain subtypes of cancer strongly suppressed chemokine production, potentially explains the molecular basis of the low T cell infiltration phenotype in the tumor subtype. Additionally, a subunit of a complex that often altered in cancer show strong involvement in cytokine induced chemokine regulation. Furthermore, we found some immune checkpoint modulators participate in modulating T cell infiltration and persistence in tumors, which dominate immunotherapy responses. From the T cell perspective, our results confirmed that certain cytoskeletal components and cell-signaling molecules can enhance or reduce the ability of T cells to move through dense extracellular matrix surrounding cancer cells. Beyond identifying such regulatory pathways, we optimized in vivo mouse models of pancreatic cancer to test how these genetic factors affect actual T cell infiltration and tumor control. These findings together provide strong evidence that both tumor “extrinsic” and T cell “intrinsic” mechanisms should be tackled to achieve better immunotherapy results.
On the tumor side, we discovered that tumor often regulate their secretion of chemokines (proteins that attract immune cells) in ways that limit T cell entry. In particular, we found high levels of a transcription factor strongly upregulated in certain subtypes of cancer strongly suppressed chemokine production, potentially explains the molecular basis of the low T cell infiltration phenotype in the tumor subtype. Additionally, a subunit of a complex that often altered in cancer show strong involvement in cytokine induced chemokine regulation. Furthermore, we found some immune checkpoint modulators participate in modulating T cell infiltration and persistence in tumors, which dominate immunotherapy responses. From the T cell perspective, our results confirmed that certain cytoskeletal components and cell-signaling molecules can enhance or reduce the ability of T cells to move through dense extracellular matrix surrounding cancer cells. Beyond identifying such regulatory pathways, we optimized in vivo mouse models of pancreatic cancer to test how these genetic factors affect actual T cell infiltration and tumor control. These findings together provide strong evidence that both tumor “extrinsic” and T cell “intrinsic” mechanisms should be tackled to achieve better immunotherapy results.
Based on the results obtained so far, we have shed new light on how tumors evade T cell infiltration, specifically by adjusting chemokine expression or by altering T cell responsiveness to dense tissue environments. These discoveries present potential targets for future intervention or patient stratification for immunotherapies.
Looking ahead, further development and validation may include advanced gene-editing strategies in human T cells and testing novel drugs that inhibit or enhance the newly identified regulators in the tumor microenvironment. Uptake of these results into practical cancer therapies will require collaboration with industry partners for commercial development and with regulatory bodies to ensure safety and efficacy. If successful, this effort could lead to improvement in immunotherapy, offering patients more effective and targeted treatment options.
Looking ahead, further development and validation may include advanced gene-editing strategies in human T cells and testing novel drugs that inhibit or enhance the newly identified regulators in the tumor microenvironment. Uptake of these results into practical cancer therapies will require collaboration with industry partners for commercial development and with regulatory bodies to ensure safety and efficacy. If successful, this effort could lead to improvement in immunotherapy, offering patients more effective and targeted treatment options.