Role of beta-2 integrins on immunoregulatory cell types for tumor immune evasion

• Applicant: Professor Dr. Stephan Grabbe
• Subject Area: Dermatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539441227

Beta(ß)2 integrins are heterodimeric surface receptors which consist of a variable alpha (CD11a-d) and a constant beta (CD18) subunit. CD11a/CD18 (leukocyte function-associated antigen-1, LFA-1) is expressed by all leukocytes, and it is the only ß2 integrin family member that is expressed by T cells. In contrast, expression of CD11b/CD18 (macrophage surface antigen-1, MAC-1), is largely confined to myeloid cell types. Both ß2 integrins engage intercellular adhesion molecule (ICAM) and thereby contribute to leukocyte migration. Further, LFA-1 is an important constituent of the immunological synapse and controls T cell activation and polarization. MAC-1 engages a number of distinct ligands and is involved in numerous immunoregulatory and signaling processes. So far, transgenic mouse strains generated to assess the immunological role of ß2 integrins displayed a global knockdown of either CD18 or of one of the different CD11 subunits. This limited their use to delineate the cell type-specific role of ß2 integrins under pathophysiological conditions. Therefore, we recently generated a mouse strain with a floxed CD18 gene locus and yielded sublines with a knockdown of ß2 integrins specifically in neutrophils and regulatory T cells (Treg), respectively. Tumor-associated neutrophils (TAN) and closely related tumor-induced granulocytic myeloid-derived suppressor cells (gMDSC) as well as Treg are the major immunoregulatory cell populations that inhibit anti-tumor immune responses within the tumor microenvironment. Interestingly, growth of B16 melanoma was significantly delayed in mice with a TAN/gMDSC- or Treg-specific ß2 integrin knockdown and a proportion of mice even remained tumor-free after inoculation with B16 melanoma cells. Tumors derived from mice with a ß2 integrin knockdown commonly displayed less Treg and increased frequencies of PD-L1 expressing tumor cells indicative of an inflamed tumor microenvironment but differed in other regards. We hypothesize that ß2 integrins are required for functional crosstalk of TAN/gMDSC and Treg and their immune-inhibitory properties. This project aims to (i) decipher the role of ß2 integrins in TAN/gMDSC and Treg for their induction, expansion, activation and immunoregulatory functions; (ii) assess the importance of ß2 integrins for the physical interaction between Treg, TAN/gMDSC, antigen presenting cells, T effector cells and tumor cells; (iii) define the gene expression profiles of tumor-infiltrating Treg and TAN/gMDSC in the course of tumor establishment and growth and (iv) evaluate the therapeutic efficacy of immune checkpoint inhibition in tumor-bearing mice that lack ß2 integrins on Treg cells and TAN/gMDSC, respectively. The results of these studies will improve our understanding on the role of ß2 integrins for the tumor-promoting activity of immunoregulatory cells.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Matthias Bros