Spatiotemporal Dynamics of Intratumoral Immune Cells Reveal the Immune Landscape in Human Cancer

Abstract

The complex interactions between tumors and their microenvironment remain to be elucidated. Combining large-scale approaches, we examined the spatio-temporal dynamics of 28 different immune cell types (immunome) infiltrating tumors. We found that the immune infiltrate composition changed at each tumor stage and that particular cells had a major impact on survival. Densities of T follicular helper (Tfh) cells and innate cells increased, whereas most T cell densities decreased along with tumor progression. The number of B cells, which are key players in the core immune network and are associated with prolonged survival, increased at a late stage and showed a dual effect on recurrence and tumor progression. The immune control relevance was demonstrated in three endoscopic orthotopic colon-cancer mouse models. Genomic instability of the chemokine CXCL13 was a mechanism associated with Tfh and B cell infiltration. CXCL13 and IL21 were pivotal factors for the Tfh/B cell axis correlating with survival. This integrative study reveals the immune landscape in human colorectal cancer and the major hallmarks of the microenvironment associated with tumor progression and recurrence.

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…Indeed, various systems-based analyses have highlighted Tfh as key modulators of the immune landscape across cancer types. 10,13 Here, we establish that Tfh are elevated in LUAD tissue and correlate with elevated plasma cells in TLOs. Furthermore, elevated levels of Tfh can be observed in Stage I tumours, and correspond to increased mutational burden and immunogenic CT antigen expression.…”

“…8 In human breast cancers and mouse models of colorectal cancer, increased Tfh correlates with increased survival. 9,10 …”

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…While follicular B cells within TLSs support humoral immunity, and can generate antibodies that recognise tumour antigens,8 they also provide costimulatory signals that drive T cell priming and expansion 48. Thus, an environment that favours Th1‐type responses at TLSs, as has been described in other types of cancer,5, 7, 14, 49 may be required to sustain anti‐tumour responses that favour improved patient outcomes. While the tumour‐associated TLSs observed in gp130 F/F mice display B and T cell compartmentalisation and germinal centre reactions, the failure to mount robust anti‐tumour responses that prevent tumourigenesis may relate to the location of TLSs.…”

“…Detection of a TLS‐associated gene signature may therefore act as a reliable prognostic indicator of patient outcome. Notably, the expression of TLS‐related genes including CXCL13 , CCL19 and CCL21 , has been linked with a good prognosis in colorectal cancer14, 15 and melanoma 13. Interestingly, expression of a 3‐gene TLS signature comprising CXCL13 , CCL19 and CCL21 was increased in patients with advanced GC.…”

“…TLSs can develop in tissues where persistent inflammation is present, and a correlation between high TLS densities and prolonged patient survival has been reported for several cancers including breast,5, 6 lung,7, 8 melanoma,9 pancreatic10 and colorectal 11, 12. TLS gene signatures, that include homeostatic chemokines such as CXCL13 , CCL19 and CCL21 , have the potential to represent prognostic indicators of cancer progression in melanoma13 and colorectal cancer 14, 15. Several studies propose that tumour‐associated TLSs provide a local environment for establishing and maintaining anti‐tumour immunity 4, 12.…”