The microenvironment of lung tumors may be essential for the anti-tumor response. The activation of the classical complement pathway and C1q is associated with shorter survival.
Why this matters
Immune checkpoint inhibitors achieve impressive responses, but do not provide a durable benefit to most patients. Further progress may come from understanding the mechanisms of response and resistance.
Summary of numerous publications and own research.
- By the time patients are treated with checkpoint inhibitors, many years may have passed with major changes in the tumors' microenvironment.
- Profiling individual patients reveals genes that are co-expressed in different microenvironments.
- NSCLC have strong signatures of genes related to T cells, B cells, myeloid cells, and tertiary lymphoid structures (TLS).
- TLS are highly organized immune aggregates, where T and B cell priming/activation probably occurs. They seem to be essential for the anti-tumor response.
- Dendritic cells (DC) in TLS modulated the clinical impact of CD8 T cells in a sample of 458 NSCLC: a high density of TLS-associated DC correlated with long-term survival (80 months vs 40 months), which also allowed a distinction of patients with high CD8+ T cell infiltration but a high risk of death (92 months vs 41 months).
- The classical complement pathway is also implicated in immunomodulation: high expression of its genes correlates with shorter overall survival in lung squamous carcinoma; NSCLC exhibit high numbers of C1q positive cells, and macrophages produce C1q in the tumor environment.
Consultant for Novartis, Medimmune, BMS, Pierre Fabre Medicaments, Servier, Adaptimmune, Immunocore, Elsalys, Dracen, OSE Immunotherapeutics, OBT. Royalties from HalioDX.