Zodiac (Case 8): CD19-Targeting Chimeric Antigen Receptor (CAR) T-Cell Cancer Therapy — What does Zodiac know about CD19?

This is the 8th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.

CD19-targeting CART immunotherapy made a splash recently (see here) as a potentially revolutionary cancer therapy. So far CART targeting CD19 has shown remarkable therapeutic effects in a small group of hematological cancer patients. Due to these initial promising results, a large number of clinical trials have now been proposed or started based on CART therapies. CD19 is one of the earliest biomarkers for CART for drug development and here I describe a set of top genes that co-express with CD19 in Zodiac.

Based on a false discovery rate of 0.01 threshold, Zodiac returns 1,343 co-expressed genes with CD19. I looked at the top 20 of them.

The usual suspects: Since this is about immunotherapy, the usual suspects show up as the top genes associated with CD19. These genes are related to immune cells, functions, defense, activations, etc in the cellular system. They are

  • CD69 This gene encodes a member of the calcium dependent lectin superfamily of type II transmembrane receptors. Expression of the encoded protein is induced upon activation of T lymphocytes, and may play a role in proliferation. Furthermore, the protein may act to transmit signals in natural killer cells and platelets.
  • GPR183 This gene was identified by the up-regulation of its expression upon Epstein-Barr virus infection of primary B lymphocytes. This gene is predicted to encode a G protein-coupled receptor that is most closely related to the thrombin receptor. Expression of this gene was detected in B-lymphocyte cell lines and lymphoid tissues but not in T-lymphocyte cell lines or peripheral blood T lymphocytes. The function of this gene is unknown.
  • CD79A The B lymphocyte antigen receptor is a multimeric complex that includes the antigen-specific component, surface immunoglobulin (Ig). Surface Ig non-covalently associates with two other proteins, Ig-alpha and Ig-beta, which are necessary for expression and function of the B-cell antigen receptor. This gene encodes the Ig-alpha protein of the B-cell antigen component.
  • ST14 The protein encoded by this gene is an epithelial-derived, integral membrane serine protease. This protease forms a complex with the Kunitz-type serine protease inhibitor, HAI-1, and is found to be activated by sphingosine 1-phosphate. This protease has been shown to cleave and activate hepatocyte growth factor/scattering factor, and urokinase plasminogen activator, which suggest the function of this protease as an epithelial membrane activator for other proteases and latent growth factors. The expression of this protease has been associated with breast, colon, prostate, and ovarian tumors, which implicates its role in cancer invasion, and metastasis.

The grand protease gene:

More about granzymes and perforin will be described in my future blog, which I plan to put together a comprehensive map between them and other CD markers using Zodiac. Potentially, I might also leak a new gene, the function of which is unknown, but might play critical roles in immune system. I hope that the new gene could help cancer drug development.

Most interestingly to me is a gene called

KYNU Kynureninase is a pyridoxal-5’s-phosphate (pyridoxal-P) dependent enzyme that catalyzes the cleavage of L-kynurenine and L-3-hydroxykynurenine into anthranilic and 3-hydroxyanthranilic acids, respectively. Kynureninase is involved in the biosynthesis of NAD cofactors from tryptophan through the kynurenine pathway.

which is a gene related to Kynurenine. From Wikipedia, “Kynurenine is synthesized by the enzyme tryptophan dioxygenase, which is made primarily but not exclusively in the liver, and indoleamine 2,3-dioxygenase (IDO), which is made in many tissues in response to immune activation.[1] Kynurenine and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation[2] and regulating the immune response.[3] Some cancers increase kynurenine production, which increases tumor growth.[1] ” Here, I suspect that there is a relationship between kynurenine pathway and CD19. Interesting, a recent paper in Blood confirmed my suspicion. The authors show that enhanced kynurenine blocks CD19-CART effect in xenocraft models and preconditioning chemotherapies suppressing IDO improve the anti-tumor effects of CD19-CART. Zodiac shows that KYNU is highly positively associated with CD19 (beta-value 11.9).  This suggests that a high KYNU expression in TCGA tumor samples (which could be mixed tumor/stroma)  could reduce CD19-related-immune-cell anti-cancer effect by its silencing mechanism of CD19-immune cells. In other words, KYNU could be a co-immune blockade gene. Zodiac also shows that KYNU is positively associated with many other CD markers, most of which are being investigated for immunotherapies in cancer. Below is a picture from Zodiac showing associations between KYNU and CD markers.

KYNU

Lastly, like the previous post on CD33, I also found genes associated with CD19 possessing important neural and cognitive functions.

  • SEPT1 This gene is a member of the septin family of GTPases. Members of this family are required for cytokinesis and the maintenance of cellular morphology. This gene encodes a protein that can form homo- and heterooligomeric filaments, and may contribute to the formation of neurofibrillary tangles in Alzheimer’s disease.
  • ARHGAP9 This gene encodes a member of the Rho-GAP family of GTPase activating proteins. The protein has substantial GAP activity towards several Rho-family GTPases in vitro, converting them to an inactive GDP-bound state. It is implicated in regulating adhesion of hematopoietic cells to the extracellular matrix. (Note: GTPase is a family of proteins that plays important roles in many functions, including including recognition of taste, smell and light.)

In the press release for a successful phase I trial for a CD19-targeting CART, it was stated that “T-cell activation causes the release of inflammatory cytokines, producing symptoms including high fevers, aches, hypotension, and, more rarely, pulmonary edema and neurologic effects such as delirium.” Delirium is an organically-caused decline from a previously attained baseline level of cognitive function. It appears that the neurological side effects of CD-marker-targeting CART might be due to the association of neurologically related genes and the CD markers.

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