SY23-1 Understanding immune checkpoint inhibitors from a viewpoint of the cancer immunobiology

Abstract

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) can restore pre-existing anti-cancer immunity and have achieved a durable clinical response across the various type of tumors including breast cancer. The success of these ICIs has turned physicians' gaze on cancer immunobiology. Cytotoxic T cells become exhausted in a series of interaction between tumors and immune cells and the clonal replacement of tumor infiltrating lymphocytes (TILs) occurred from the peripheral blood. TCF1-positive stem-like T cells retain high proliferation potential and self-renewal in antigen presenting cell (APC)-niches of the primary tumors. Once these pre-exhausted T cells were reinvigorated by ICIS, they could be expanded and differentiated to functional CD8-positive effector T cells. Draining lymph node (DLN) is the secondary lymphoid organ where the naive T cells are primed by APCs and differentiated to effector T cells. The therapeutic effects of PD-L1 blockage were completely canceled in mice undergoing completion of axillary lymph node dissection. Moreover, tumor-positive DLNs showed a lower T cell receptor (TCR) diversity than tumor-negative ones and had similar TCR repertoires to TILs. These findings suggested that antigen-specific T cell clones could be enriched in tumor-positive DLNs and recruited from the distal sites to the tumor microenvironment. Accumulating results provide the evidence that neoadjuvant therapy combined with ICIs might generate an immune response regardless of PD-L1 status in early-stage triple negative breast cancer and a greater ICI benefit appeared in patients with tumor-positive DLNs. Deep understanding of the underlying immunobiology might lead to biomarker-driven strategies to identify patients who are more likely to experience a favorable effect from ICIs. I will summarize emerging evidences from T cell basic science to clinical practice in the field of cancer immunotherapy.