Tumour-reactive heterotypic CD8 T cell clusters from clinical samples - Nature

"An increasing body of evidence suggests that, in addition to the type, density and state of immune cells in the tumour microenvironment (TME), their proximity to cancer cells also influences immunotherapy outcomes1,2,3,4,5. For example, in two melanoma studies, favourable responses to immune checkpoint inhibitors are associated with either higher densities of CD8+ tumour-infiltrating lymphocytes (TILs) within a distance of 20 μm of melanoma cells5 or a higher proportion and closer proximity of (proliferating) antigen-experienced CD8+ T cells to the tumour cells6."

"Similarly, upon anti-PD-1 and chemoradiotherapy, a higher proportion of on-treatment PD-1+CD4+ and CD8+ T cells within 100 μm of tumour cells predicts longer overall survival in oesophageal cancer7, while, in locally advanced cervical cancer, progression-free patients show closer proximity of CD3+ TILs to PD-L1+ tumour cells8. Furthermore, an automated image classifier characterizing interactions between TILs and non-TILs can predict immunotherapy outcome9."

Proximity of immune cells to cancer cells is a critical determinant of immunotherapy outcomes in addition to immune cell type, density and state. In melanoma, higher densities of CD8+ TILs within 20 μm or closer proximity of proliferating antigen-experienced CD8+ T cells correlate with favourable responses to immune checkpoint inhibitors. In oesophageal cancer, a higher proportion of on-treatment PD-1+ CD4+ and CD8+ T cells within 100 μm predicts longer overall survival after anti-PD-1 and chemoradiotherapy. Locally advanced cervical cancer shows progression-free patients with closer CD3+ TIL proximity to PD-L1+ tumour cells. Cytotoxic T cells engage targets via TCRs and immunological synapses, and structural and functional avidity, successive interactions, and dynamic contacts are important for tumour cell elimination. Single-cell sequencing confirms the importance of direct interactions and can reveal additional information when cells are analyzed together, such as circulating tumour cells associated with neutrophils exhibiting increased cell cycle activity.

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