Combination of anti-CD40 and anti-PD1 revert M2 polarization to limit tumor growth in a genetically engineered blander cancer mouse model

Abstract

Abstract Bladder cancer (BCa) represents the fourth most common cancer in men with a poor patient prognosis for advanced disease. About 75% of patients present non-muscle invasive BCa (NMIBC) and 25% present muscle invasive BCa (MIBC) or metastatic disease. Although BCG immunotherapy is a common treatment of BCa, the dynamics of immune cell infiltration and its relevance for disease outcome are still not well understood. We took advantage of a genetic based mouse model of MIBC to obtain a profound understanding of the immune contexture over tumor development. P53Fl/Fl/PTENFl/Fl mice were injected with Cre recombinase-expressing adenoviral vectors directly into bladder by micro-surgery. We observed the presence of NMIBC, MIBC and the development of metastases at 5, 9 and 13 weeks after vector injection, respectively. As tumor evolves, we observed a transition from an anti-tumoral microenvironment (MHCIIhigh TAM, CD4 and CD8 TILs) to a pro-tumoral one (MHCIIlow TAM and MDSC), going along with an increased expression of PD-1 by T cells and accumulation of regulatory T cells. After testing various immunotherapy tretaments on mice with MIBC, we found out that combination of αCD40+αPD1 increases CD8 TILs infiltration and IFNg production, re-polarized TAM toward a M1-like phenotype and increased the survival of the mice.