Dynamic CEACAM1 expression enhances protection of melanoma cells from specific ongoing immune attack

Abstract

Tumor Infiltrating Lymphocytes (TIL) provide an exciting platform for cancer immunotherapy. We have previously shown that CEACAM1 homophilic interactions inhibit natural killer cells, cytotoxic and helper T cells. Importantly, CEACAM1 is present on virtually all human TIL following clinical preparation protocols, as well as on 70% of melanoma surgical specimens, suggesting that CEACAM1 impairs in vivo the anti‐tumor response of TIL. Supporting this hypothesis, it has been shown that the presence of CEACAM1 on primary melanoma strongly predicts poor prognosis. Further, TIL persist and function in vivo for days and remarkably, the prolonged co‐incubation of reactive TIL with their cognate melanoma targets results in increased CEACAM1 expression by the surviving tumor cells, which is functional and confers enhanced resistance to fresh TIL. Interestingly, this is an active process mediated by a TIL‐derived IFNγ, although partial role for immune selection cannot be completely excluded. Furthermore, we show that increased CEACAM1 directly enhances proliferation of melanoma cells. Therefore, dynamic expression of CEACAM1 might be employed by melanoma cells in vivo to evade ongoing destruction by TIL and proliferate. This may be an explanatory example for a mechanism of disease recurrence. In conclusion, CEACAM1 plays key role in the development and progression of melanoma and may therefore be an attractive target for development of novel immunotherapeutic interventions. GM is supported by The Ella Institute, ICRF and ICA foundations.