Tumour Infiltrating (TINK) and Tumour Associated (TANK) Natural Killer cells: role in colorectal cancer (CRC) progression and angiogenesis.

Tumor infiltrating immune cells often show a skewed phenotype that reflects attenuation of anti- tumor activity and enhancement of pro-tumor and pro-angiogenic activities. We previously reported that NKs from Non Small Cell Lung Cancer patients are able to acquire the decidual-like CD56+CD16-VEGFhighPlGFhighIL- 8+IFNlow phenotype and promote angiogenesis in vitro. Here, we extended our findings to colorectal cancer (CRC) to verify whether the TINK/TANK polarization may represent a crucial hallmark of solid tumours. We found that CD56+CD16- NK cells predominate in CRC adjacent and tumor tissues, show decreased NKG2D surface expression and impaired cytotoxicity. Further, TINK/TANKs from CRC patients express the decidual NK markers CD9 and CD49a. Secretomic and flow cytometry on CRC peripheral blood NK cells revealed the up-regulation of several pro-angiogenic factors. Molecularly, the STAT-3 and STAT-5 pathway activation was observed in TANKs, suggesting the potential involvement of these signaling pathways in the angiogenic switch. CM by FACS sorted NKs from CRC patients were able to induce HUVEC proliferation, migration, adhesion and the formation of capillary like structures. These functional alterations are related with molecular changes in HUVECs, that include the phosphorylation of AMPKα, GSK-3, P70 S6 Kinase and S6 ribosomal protein. Our data demonstrate that TINK/TANKS from CRC patients are switched toward a proangiogenic/ pro-tumor phenotype and function. We propose that TINK/TANKs could represent a relevant biomarker for CRC progression.