Abstract 1342: Roles for CD40 ligation in tumor-macrophage interaction and tumor metastasis

Abstract

Abstract Macrophages are now known to play multiple roles in the progression and metastasis of many solid tumors. Although tumor-derived cytokines play a role in stimulating cytokine production by the macrophages, the extent of tumor-macrophage cross-talk remains to be explored. We have previously demonstrated that CD154:CD40 interactions are a dominant mechanism of contact-dependent communication between a variety of cell types. We therefore initiated a study of the role of CD154:CD40 interactions in tumor-macrophage interactions. Flow cytometric analysis reveals CD154 expression on 3LLC carcinoma cells. In corroboration of previous studies, co-culture of supernatants of tumor cell cultured with normal macrophages stimulated moderate cytokine production and this was equally effective with both CD40+/+ and CD40-/- macrophages. Co-culture of paraformaldehyde-fixed tumor cells with normal macrophages stimulated cytokine production by the macrophages, indicating that a cell contact dependent mechanism was also involved in the stimulation of macrophages by the tumor cells. Implantation of 3LLC tumors subcutaneously in CD40+/+ and CD40-/- mice resulted in similar growth of the primary tumor mass. However, no lung metastases were detectable in the CD40-/- mice. Bone marrow chimeric mice were generated by reconstituting irradiated CD40+/+ mice with either CD40+/+ or CD40-/- bone marrow. Nine weeks later, the splenic and peripheral blood leukocytes were >94% donor derived. Both recipients of CD40+/+ and CD40-/- bone marrow displayed similar growth of the primary tumor and similar frequency of lung metastases, indicating that CD40 expression by bone marrow derived macrophages was not critical for tumor metastasis. The study demonstrates that ligation of CD40 on hematopoietic and non-hematopoietic cells may play critical roles in tumor progression and metastasis. This research was supported by grants from the Kentucky Lung Cancer Foundation (J.S.) and the Susan G. Komen Race for the Cure (R.S.) and by an NRSA T32 Postdoctoral Training Grant (K.R.) and a Ruth Kirschstein T31 Predoctoral Fellowship (C.G.). Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1342.