Cancers account for nearly 10 million deaths and 20 million new cases globally in 2020. Whereas routine care and some immunotherapies are available, high death rates and low-quality of life with cancers demand the discovery of efficacious targets for novel therapeutic development. T cells play a fundamental role in suppressing cancer progression. However, inducing protection with conventional T cells is challenging due to the need for identifying peptide antigens that ought to match individual genetics. Independent of individual genetics, mucosal-associated invariant T (MAIT) cells respond to cancer metabolites and kill cancer cells, such as leukemia and glioma cells, as preliminarily suppor...

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Cancers account for nearly 10 million deaths and 20 million new cases globally in 2020. Whereas routine care and some immunotherapies are available, high death rates and low-quality of life with cancers demand the discovery of efficacious targets for novel therapeutic development. T cells play a fundamental role in suppressing cancer progression. However, inducing protection with conventional T cells is challenging due to the need for identifying peptide antigens that ought to match individual genetics. Independent of individual genetics, mucosal-associated invariant T (MAIT) cells respond to cancer metabolites and kill cancer cells, such as leukemia and glioma cells, as preliminarily supported by my and others' studies. Thus, MAIT cells will likely provide a promising and novel anticancer T cell candidate to treat various cancers. However, critical problems are the unknown cancer cell metabolites and MAIT cell clones to elicit anticancer MAIT cell responses. To solve these problems, we will test the hypothesis that cancer metabolites stimulate MAIT cell clones to kill leukemia and glioma cells by pursuing two specific aims. In Aim 1, we will use the extracted cancer cell metabolites to stimulate MAIT cells from healthy donors compared with cancer patients and stimulate MAIT TCR-engineered T cells for cancer cell-killing. In Aim 2, we will identify cancer metabolites using our established functional metabolomics to stimulate MAIT cells from cancer patients and MAIT TCR-engineered T cells for cancer cell-killing. Results will generate protective anticancer MAIT cell clones, MAIT TCR-engineered T cells, and cancer metabolite antigens to kill myelogenous leukemia and glioma cells, allowing future tests of pan-anticancer effects in animals and humans. The major impact is that this study will reveal a novel paradigm of pan-anticancer unconventional T cells and identify cancer metabolite stimulators with MAIT cell TCR for eliciting anticancer immunity.

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