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Brianna Malaya Regan
Pronouns
She/Her/Hers
Job Title
Technical Research Assistant
Academic Rank
Department
Neurology
Authors
Alexandra Schnell, Linglin Huang, Brianna M.L. Regan, Vasundhara Singh, Dominik Vonficht, Alina Bollhagen, Mona Wang, Yu Hou, Lloyd Bod, Vijay K. Kuchroo
Principal Investigator
Vijay K. Kuchroo
Research Category: Cancer
Tags
Immune checkpoint blockade (ICB) treatment has revolutionized cancer therapies, yet current ICB response rates are still low. This suggests the need to discover novel immune checkpoint treatments with higher potency, more efficacy, lower toxicity rates, and fewer immune-related adverse events (irAEs) in cancer patients. Importantly, significant numbers of patients treated with ICB develop irAEs, limiting ICB treatment efficacy. Our lab has discovered a previously undescribed checkpoint molecule (AB1) that is co-expressed with other checkpoint molecules on exhausted T cells infiltrating tumours. Deletion of AB1 in all murine cells resulted in enhanced anti-tumour immunity, as well as increased resistance to developing Experimental Autoimmune Encephalomyelitis (EAE). We conditionally deleted AB1 from different cell types and tested for development of anti-tumour immunity and autoimmunity. AB1 appears to be critical in regulating cytotoxic CD8+ T cell responses in that selective loss of AB1 in CD8+ T cells induces highly cytotoxic effector T cell responses, leading to tumour growth inhibition. Furthermore, using EAE models in an autoimmune setting, deletion of AB1 on myeloid cells suppresses autoimmune reaction. Our findings indicate that checkpoint molecule AB1 may be a potential target for anti-tumour immunity while protecting against irAEs and autoimmunity that are prevalent with current ICB therapies.
One of the key immune cells that fights cancer is the T cell, which can attack and kill cancer cells. Once cancer cells are killed, T cells are halted from further action by activation of a checkpoint molecule. However, cancer cells can activate checkpoint molecules on immune cells and evade attacks from T cells. Immune checkpoint blockade (ICB) therapy is a cancer treatment whereby immunotherapy drugs block checkpoint molecules on T cells, allowing them to remain “on” and kill cancer cells. While this is good for treating cancer, allowing T cells to remain engaged can cause them to attack non-cancerous human cells, causing unwanted autoimmune effects. Our lab has discovered previously unknown checkpoint molecule, AB1, that is expressed on T cells. In mice, deleting AB1 from all cells resulted in smaller tumours and less severe experimental autoimmune disease symptoms. Deleting AB1 off “killer” T cells gave smaller tumours than normal mice. Additionally, deleting AB1 off myeloid cells, which have various roles in the immune system, reduced autoimmune reactions in mice with autoimmune disease conditions. Our findings indicate that checkpoint molecule AB1 is a potential target for cancer treatment that may prevent autoimmunity that is prevalent with current ICB therapies.
