Professor University Hospital Erlangen Erlangen, Germany
Disclosure(s):
Susetta Finotto, PhD: No financial relationships to disclose
Introduction/Rationale: Immune checkpoint inhibitors targeting the interaction between PD1 and PDL1 are effective for immunotherapy in non-small cell lung cancer (NSCLC), which is the leading cause of cancer related death in the world. However, only subgroups of patients respond to therapy suggesting the existence of resistance mechanisms. Blimp-1 is a transcription repressor that interacting with other transcription factors in lymphocytes regulate their cellular fate.
Methods: In this study,we analyzed post-surgery lung tissues and peripheral blood cells from patients with Non Small Cell Lung Cancer (NSCLC) and control subjects by using western blot, immunohistochemistry, ELISA, multiplex cytokine and qPCR analysis. Moreover, we analyzed in a murine model of NSCLC, the role of Blimp1 in T cells after targeting of Blimp-1 in T cells expressing lymphocyte-specific-protein tyrosine kinase (Lck), a kinase crucial for T cell receptor signaling. In addition we blocked PD1 in this murine model of lung cancer.
Results: Here, we found progressive increased Blimp1 expression in the tumoral region of NSCLC patients. In PBMCs, Blimp1 was expressed in CD8+ T cells but predominantly in immunosuppressive Foxp3+ Treg cells. Targeting PD1 in PBMCs reduced Blimp1. In a murine model of NSCLC, T cell targeting of Blimp-1 resulted in reduced tumor load, suppressed lung Foxp3+ Treg cells and induced T-bet+ T effector cells producing IFN-gamma. Furthermore, RNA sequencing of T cells showed an induction of Th1 and Tc1 markers and PD1 in the absence of Blimp1. Targeting PD1 on a Blimp-1 deficiency in T cells in tumor resulted in induction of cytotoxic and effector T cells.
Conclusion: These data indicate that the tumor microenvironment induces Blimp-1 in immunosuppressive Treg and CD8+ T effector cells, thereby limiting the therapeutic efficacy of anti-tumor immune responses. Targeting of Blimp-1 emerges as a novel concept to suppress immune evasion during anti-PD1 immunotherapy in lung cancer.
