Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti–PD-1 treatment

TLDR

Cancer immunotherapy is promising, yet durable responses are achieved in only a minority of patients. The study examines whether tumor‑associated macrophages drive the immune‑excluded phenotype that limits T cell infiltration. In human and murine tumors, CD8 T cells are impeded from infiltrating tumor nests by persistent interactions with TAMs; removing TAMs restores T cell migration, enhances anti‑PD‑1 efficacy, and supports a combined TAM‑targeting and checkpoint blockade strategy.

Abstract

Significance Cancer immunotherapy is a promising therapeutic intervention. However, complete and durable responses are seen in only a fraction of cancer patients. A key factor that limits therapeutic success is the lack of T cells in tumor cell regions, a profile termed “immune-excluded.” Here, we provide evidence that tumor-associated macrophages (TAMs) are an important determinant of the establishment of a T cell-excluded tumor phenotype. In human and murine tumors, we found that CD8 T cells poorly migrate and invade tumor nests due to long-lasting interactions with TAMs. The depletion of TAMs restores T cell migration and infiltration into tumor islets and improves the efficacy of anti–PD-1 immunotherapy. This study highlights the rationale of combining approaches targeting TAM and immune checkpoint proteins.