Student Theses and Dissertations
Mechanisms of Evasion: Anti-Tumor Immune Suppression & TRNA-Dependent Growth in Cancer Metastasis
Date of Award
Doctor of Philosophy (PhD)
Metastatic disease presents diverse therapeutic challenges for cancer patients, clinicians, and scientists. Cancer cells have developed sophisticated mechanisms of evasion to survive the selective pressures provided by the metastatic cascade. Two themes of success encompass modulating their surrounding microenvironment, or manipulating cell autonomous regulatory programs not intended for differentiated somatic cells. Both challenges are addressed in this body of work which focus on gastrointestinal and breast cancer metastasis. During cancer progression, tumour cells employ mechanisms that suppress both adaptive and innate immune responses. While our understanding of the molecular basis of adaptive immune suppression by cancer cells has led to the development of transformative immune checkpoint therapies, our knowledge of the molecular basis of innate immune suppression is less developed. Such innate immune suppressive mechanisms are thought to be especially active in gastrointestinal cancers— prevalent malignancies that are overall highly refractory to approved immune therapies. We describe an elegant molecular mechanism employed by pancreatic and colorectal cancer cells for repression of innate anti-tumour immunity. We observe that the creatine kinase brain-type (CKB) enzyme, which is over-expressed by colorectal cancer cells suppresses anti-tumor immunity. CKB localizes to the surface of cancer cells and can also be released into the extracellular space. This kinase enzymatically consumes extracellular ATP—a potent immune stimulatory Danger Associated Molecular Pattern (DAMP) molecule—from the tumor microenvironment. ATP hydrolysis by CKB generates ADP, an immune suppressive molecule. The action of this enzyme can thus concomitantly deplete an immune stimulatory molecule and generate an immune suppressive metabolite. Consistent with this, tumoral CKB suppresses dendritic cell activation, T-cell activation and B cell infiltration. Moreover, CKB suppresses immunity against primary and metastatic pancreatic tumors and impairs establishment of immunological antitumoral memory. To uncover new modalities of cell autonomous regulation by cancer cells, in the midst of technical development to measure small RNA species, tRNAs have emerged as significant regulators of gene expression. The human genome contains 61 codons that are recognized by distinct transfer RNAs (tRNAs). We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons become modulated in opposing directions during breast cancer progression. Specifically, tRNAIle UAU is upregulated whereas tRNAIle GAU is repressed as breast cancer cells attain enhanced metastatic capacity. TRNAIle UAU promoted and tRNAIle GAU suppressed metastatic colonization. These effects were mediated by codon-dependent translation of growth promoting or suppressing genes via cognate codon-dependent interactions. We also make the surprising observation that one isoleucyl tRNA can competitively impair translational decoding of synonymous codons by the other tRNA. Our findings uncover a specific isoacceptor tRNA pair that act in opposition—modulating distinct gene networks that contribute to an organismal phenotype. The degeneracy of the genetic code can thus be biologically exploited by human cancer cells via tRNA isoacceptor shifts and tRNA-mediated translational antagonism at the ribosome. Investigating fundamental cellular programs and tumor microenvironment interactions will enable more opportunity through knowledge to therapeutically target metastatic disease.
Noble, Lisa Brooke, "Mechanisms of Evasion: Anti-Tumor Immune Suppression & TRNA-Dependent Growth in Cancer Metastasis" (2020). Student Theses and Dissertations. 692.
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy