Targeting Immunosuppressive Myeloid Cells and Exhausted CD8+ T Cells Overcomes Radioresistance in NSCLC

Abstract

Although stereotactic body radiation therapy (SBRT) has achieved great success in the treatment of non-small cell lung cancer (NSCLC), local relapses still occur and abscopal effects are rarely seen even when combined with immune checkpoint blockers (ICBs). Therefore, it is necessary to thoroughly understand the immune responses after SBRT. We characterized the dynamic changes of tumor-infiltrating immune cells at early and late time points after SBRT in a therapy-resistant murine tumor model using single-cell transcriptomes and T-cell receptor sequencing. At the early stage, the innate and adaptive immune systems were activated, including activation of NKs and NKTs, and infiltration of cytotoxic CD8+ T cells. At the late stage, however, the tumor immune microenvironment (TIME) shifted into immunosuppressive properties, containing enrichment of immunosuppressive tumor-associated neutrophils (TANs), M2-like tumor-associated macrophages (TAMs), and terminal exhausted CD8+ T cells. Furthermore, our study revealed that inhibition of CD39 combined with SBRT preferentially reinvigorated exhausted CD8+ T cells and promoted their proliferation, infiltration, and cytotoxicity. Meanwhile, it also promoted M1-like macrophage infiltration and DCs maturation. On the other hand, consequently increased infiltration of immunosuppressive myeloid cells after SBRT could be a potential mechanism mediating CD8+ T cell dysfunction. Moreover, we found that combination treatment with anti-VISTA and SBRT synergistically reduced immunosuppressive myeloid cells, containing TANs, M-MDSCs, and M2-like TAMs, and further activated CD8+ T cells. Clinically, high VISTA expression was associated with poor prognosis in NSCLC patients. Altogether, our data provides deep insight into acquired resistance to SBRT from an immune perspective and presents rational combination strategies.