PhD Student Cancer Institute, University College London London, England, United Kingdom
Introduction: Multiple Myeloma (MM) is associated with skewed immune cell activation and function. Univariate analyses show individual immune cells are altered in precursor states. However, a comprehensive model linking immune processes during progression and their interaction with tumour cells is lacking.
Methods: We generated a large dataset of published and newly-generated bone marrow single-cell RNA sequencing (scRNAseq): >914,000 cells from patients with MM MM (n=46), the precursor conditions MGUS (n=19) and SMM (n=28) and non-cancer controls (n=58). scvi was used integration, and both regression and unsupervised approaches for differential abundance. Tumour cells were identified via their unique combination of immunoglobulin genes.
Results: We characterise two immune profiles (immunotypes), composed of immune cells which co-associate in abundance.
The first immunotype reflected aging-like differentiation including a loss of naive T cells, B cells, and haematopoietic progenitors; and an enrichment of differentiated T cells, NK cells and activated dendritic cells (DCs). This immunotype correlated with age in controls (R=-0.68, P< 0.001), reflecting healthy aging. This immunotype was enriched in MM patients independent of age (P=0.004), rising with advancing severity (MGUS to SMM to MM), such that patients had increasingly prematurely-aged immune composition. This immunotype correlated with tumour MHC class I (MHC-I) expression (R=0.43, P = 0.007), which fell between SMM to MM (HLA-C, P=0.029), meaning patients whose tumours expressed the lowest MHC-I were the most immunosenescent. Within this immunotype, a clonal effector memory CD8+ T cells expressing a genes enriched in non-viral clones (GZMB+ITGB1+) correlated with tumour MHC-I (R=0.33, P=0.002).
The second immunotype was composed of inflammatory cell types, including Interferon Stimulated Gene (ISG)-expressing T and B cells, inflammatory CD4+ regulatory T cells and plasmacytoid DCs. This immunotype was enriched in osteoarthritic non-cancer controls alongside MM (but not MGUS or SMM) patients. This immunotype was most pronounced in highly-infiltrated marrows (aspirate CD138+ %) and those with the greatest proportion of proliferating tumour cells (% MKI67+ tumour), suggesting tumour growth-associated inflammatory niche remodelling. ISG+ effector T cells enriched in infiltrated marrows shared T cell receptors with cytotoxic terminal memory T cells accumulating within the aging-like immunotype, suggesting a link between these two immunotype processes.
Conclusions: We unify the variation in bone marrow immune architecture in the progression to Myeloma into two key processes (immunotypes). Age-independent, tumour MHC-I-dependent immunosenescent-like differentiation could indicate an accumulation of historical anti-tumour responses leading up to progression. Osteoarthritic-like inflammatory cells enriched in MM reflecting local tumour burden and growth may possibly represent acute anti-tumour responses occurring in situ.
