HHLA2 and TMIGD2 are two novel members of the B7-CD28 immune checkpoint family
Chinai, Jordan Manek
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HHLA2 is a newly identified B7 family member that inhibits T cell function. Little is known about its expression and what biological functions it serves. Here we extensively assess protein expression of HHLA2 in a wide array of normal human tissues as well as cancerous tissues. We found that HHLA2 is expressed in relatively few normal tissues, but could be detected in a diverse set of cancers. We also show that its expression in triple negative breast cancer is significantly correlated with the stage of disease as well as lymph node metastasis. We hypothesize that HHLA2 functions as a co-inhibitor of T cells in the tumor microenvironment. We believe this function promotes tumor survival and progression.;The receptor(s) for HHLA2 that mediate its function on T cells are important to know from a mechanistic perspective. We identified and screened a list of candidate receptors from the immunoglobulin family that had a phylogenetic profile similar to HHLA2. Using these criteria and experimental studies, we identified TMIGD2 as a receptor for HHLA2. The function of this receptor interestingly appears to be stimulatory and it is likely that other receptors have yet to be identified.;This work also sought to understand the mechanisms regulating HHLA2's expression and HHLA2's role in the tumor microenvironment. We demonstrate that HHLA2 expression appears to be upregulated in vivo and is lost in vitro. We show that hypoxia, anchorage-independent growth, and cytokines are all factors that can upregulate HHLA2 expression on human cancer cell lines. It is likely that a combination of these factors contribute to HHLA2 expression in patient tumors.;Finally, to understand the function of HHLA2 in the tumor microenvironment we developed an in vivo humanized mouse model. This model utilizes human tumor xenografts that naturally express HHLA2 and derivatives we generated using CRISPRCas9 that are genetically deficient for HHLA2. The model also incorporates human immune cells that are capable of anti-tumor activity. Using this model, we have assessed the phenotypic effects that tumor-expressed HHLA2 has on tumor-infiltrating lymphocytes. Preliminary results from this model suggest a suppressive role for HHLA2 in the tumor microenvironment and support targeting this molecule as a potential treatment for cancer.