Myeloid-instructed CD14 ⁺ CD4 ⁺ T cells within the tumor microenvironment are associated with TNF⍺ signaling and prolonged survival in non-small cell lung cancer

Immune cells from the adaptive and innate immune systems coexist in the tumor immune microenvironment (TME) to mediate tumor cell immunosurveillance and prevent tumor relapse. Relapse-free survival after surgical resection is heterogeneous in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), the two major subtypes of non-small cell lung cancer. Yet, little is known about the composition and spatial organisation of the TME that could explain the different prognoses for lung cancer patients. Using spatial multi-omics analyses, we show that LUAD and LUSC have distinct TMEs and that neutrophil-enriched tumors are associated with worse survival, while the accumulation of myeloid-instructed CD14 ⁺ T cells in the tumor core was associated with prolonged patient survival. CD14 ⁺ CD4 ⁺ T cells express prototypic markers of myeloid cells and were found to be clonally expanded tumor-specific activated T cells. TNFα signaling was activated in tumors with high infiltration of CD14 ⁺ CD4 ⁺ T cells in the tumor core. Our results demonstrate that innate immune cells impact adaptive immune cell activity to support the deployment of discrete T cell populations with anti-tumor activity.