Intratumoral Immune Cell Infiltration Is Spatiotemporally Regulated

Infiltration of T-helper 1 (Th1) cells and cytotoxic T cells correlates with diminished tumor recurrence and prolonged survival in colorectal cancer. However, the contribution of other immune subpopulations to clinical outcome and the dynamics of immune-cell infiltration during tumor progression remain poorly understood. Bindea and colleagues used an integrative, systems approach and defined the immunome, a compendium of highly expressed genes specific for adaptive and innate immune-cell subpopulations, to evaluate infiltrating immune-cell densities, which were validated via immunohistochemical staining of tumors. Analysis of the immunome in colorectal cancer samples identified two clusters of patients characterized by distinct immune gene signatures and clinical outcomes. Expression of markers of T cells, B cells, and T-follicular helper (Tfh) cells, which promote B-cell immune responses, was increased in patients with prolonged disease-free survival, and increased intratumoral densities of Tfh cells and B cells correlated strongly with good prognosis, supporting a role for these adaptive immune cells in protection against tumor recurrence. In addition, immune infiltrate composition varied between the tumor center and invasive margin and evolved with tumor progression; the density of most T-cell subsets decreased with tumor grade, whereas Tfh- and B-cell markers increased in late-stage tumors. Infiltration of B cells and Tfh cells was regulated in part by chemokine (C-X-C motif) ligand 13 (CXCL13), as genomic CXCL13 deletion in colorectal tumors was associated with increased risk of tumor relapse and reduced density of B cells and Tfh cells. Furthermore, inhibition of CXCL13 signaling in an endoscopic orthotopic mouse model of colorectal cancer accelerated tumor growth, whereas treatment with CXCL13 promoted tumor rejection. These findings provide insight into the spatiotemporal control of the immune landscape in colorectal cancer and establish B cells and Tfh cells as critical regulators of tumor recurrence and survival.

Bindea G, Mlecnik B, Tosolini M, Kirilovsky A, Waldner M, Obenauf AC, et al. Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. Immunity 2013;39:782–95.