HHLA2 functions as a T cell coinhibitory molecule as it suppresses proliferation and cytokine production of both human CD4 and CD8 T cells.HHLA2 is constitutively expressed on the surface of human monocytes and is induced on B cells after stimulation.Unlike PD-L1 and B7–1 though, HHLA2 is not inducible on T cells. The differences in expression on immune cells suggest that HHLA2 could be involved in immune regulation at a different functional level than other B7 family members. Using immunohistochemistry with an HHLA2 monoclonal antibody, we have recently found that HHLA2 is not expressed in most human tissues, except the placenta, kidney, intestine, gall bladder, and breast. Expression of HHLA2 in the placenta and the intestines is interesting as it may help fetal-maternal immune tolerance or control intestinal inflammation, respectively. Importantly, we have shown many human cancers overexpress HHLA2 including cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus.Moreover, in a small cohort of human triple-negative breast cancer (TNBC) patients, higher expression of HHLA2 on cancer cells was associated with increased lymph node metastases.6 The wide expression of HHLA2 in human cancers and its association with more invasive disease in the TNBC cohort suggest that HHLA2 potentially plays an important role in cancer evolution and metastases through immune suppression.
Xiao Y, Freeman GJ. A new B7:CD28 family checkpoint target for cancer immunotherapy: HHLA2. Clinical cancer research?: an official journal of the American Association for Cancer Research. 2015;21(10):2201-2203.