PO-297 PLEXINA4 plays a role in cancer progression and immune cell infiltration

ABSTRACT Introduction Immune cells play a major role in tumour progression, metastasis and response to anti-cancer therapies. Indeed, escape from the immune system is a hallmark of cancer. Plexins are attractive/repulsive guidance molecules in the central nervous system that are also expressed in some immune cells. Starting from our previous observations that Sema3A/Nrp1 underpin a pathway that is indispensable for the immunosuppressive phenotype of tumor-associated macrophages (TAMs), we investigated how the expression of the Sema3A co-receptor PlexinA4 in stromal cells influences tumour progression and immune cell infiltration. Material and methods Lung, breast and brain tumour mouse models were used in both full PlexinA4 KO mice as well as in a PlexinA4 chimeric model. Immune cells infiltration and/or localization in the tumour were accessed by FACs and IHC. FACs-sorting was used to isolate tumour infiltrating immune-cells that were then evaluated by qRT-PCR. Results and discussions Using sorted tumor-associated immune cells and their respective non-tumour associated counterparts, we found that PlexinA4 is upregulated in tumor-infiltrating immune cells, prompting us to explore the role of plexin signalling cascade in these cells. Using PlexinA4 full KO mice, we first found that PlexinA4 deficiency in the stroma reduces tumour growth. Additionally, we generated a chimeric mouse model, where only the immune system is affected by the depletion of PlexinA4, and we observed a reduction of tumour growth in various subcutaneous and orthotopic cancer models, such as lung, breast and brain tumours. This reduction in tumour growth was accompanied by an increased infiltration of Cytotoxic T cells (CTLs). Conclusion Together, our results point to the possible use of PlexinA4 blocking antibodies as a new anti-tumour immunotherapy, alone or in combination with standard immune checkpoint inhibitors and chemotherapy regimes in refractory tumours.