Immune mechanisms orchestrate tertiary lymphoid structures in tumors via cancer-associated fibroblasts

Abstract

Tumor-associated tertiary lymphoid structures (TA-TLS) are associated with enhanced patient survival and responsiveness to cancer therapies, but the mechanisms underlying their development are unknown. We show here that TA-TLS development in murine melanoma is orchestrated by cancer-associated fibroblasts (CAF) with characteristics of lymphoid tissue organizer cells that are induced by tumor necrosis factor receptor signaling. CAF organization into reticular networks is mediated by CD8 T cells, while CAF accumulation and TA-TLS expansion depend on CXCL13-mediated recruitment of B cells expressing lymphotoxin-a 1 b 2 . Some of these elements are also overrepresented in human TA-TLS. Additionally, we demonstrate that immunotherapy induces more and larger TA-TLS that are more often organized with discrete T and B cell zones, and that TA-TLS presence, number, and size are correlated with reduced tumor size and overall response to checkpoint immunotherapy. This work provides a platform for manipulating TA-TLS development as a cancer immunotherapy strategy.

Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer

“…However, the mechanisms underlying TLS development remain unclear. Rodriguez et al found that the organization of cancer-associated fibroblasts into reticular networks depends on tumor necrosis factor receptor signaling, which acts as a lymphoid tissue organizer [ 83 ]. Cancer-associated fibroblasts secrete CXCL13 to recruit CXCR5 + B cells expressing lymphotoxin-α1β2, which expands TLSs in the tumor microenvironment.…”

“…Rodriguez et al studied cancer-associated fibroblasts to determine the effects of TLSs in a melanoma and colon adenocarcinoma mouse model [ 83 ]. Anti-PD-L1 and a combination of anti-PD-1 and anti-CTLA4 both increase the formation of TLSs in the tumor microenvironment, resulting in reduced tumor growth, and increased T cell recruitment to the tumor, as indicated by the formation of discrete T cell and B cell zones.…”

Immune function and dysfunction are determined by lymphoid tissue efficacy

“…In autoimmune disorders, TLSs are associated with production of the autoantibodies that drive disease progression; conversely, TLS formation correlates with good patient outcomes for many cancer types, suggesting that TLSs potentially promote anti-tumour immune responses ( Pipi et al, 2018 ). Similarly to lymph nodes, TLSs can exhibit segregated B- and T-cell zones ( Da Graça et al, 2021 ; Rodriguez et al, 2021 ), and are supported by stromal cells including FDCs, endothelial cells and fibroblasts ( Da Graça et al, 2021 ; Mitsdoerffer and Peters, 2016 ). The mechanisms of TLS initiation are not fully understood, but are likely to be driven by infiltrating cells and context-dependent inflammatory cues ( Mitsdoerffer and Peters, 2016 ; Rodriguez et al, 2021 ).…”

“…Similarly to lymph nodes, TLSs can exhibit segregated B- and T-cell zones ( Da Graça et al, 2021 ; Rodriguez et al, 2021 ), and are supported by stromal cells including FDCs, endothelial cells and fibroblasts ( Da Graça et al, 2021 ; Mitsdoerffer and Peters, 2016 ). The mechanisms of TLS initiation are not fully understood, but are likely to be driven by infiltrating cells and context-dependent inflammatory cues ( Mitsdoerffer and Peters, 2016 ; Rodriguez et al, 2021 ). Similarly to lymph node development, FAP + stromal cells can initiate lymphatic aggregates in response to inflammation ( Denton et al, 2019 ), requiring the presence of lymphotoxin for TLS formation and maintenance ( Mitsdoerffer and Peters, 2016 ).…”

“…During influenza virus infection, the presence of type I IFNs and IL-17 has been linked to the presence of TLSs ( Denton et al, 2019 ; Rangel-Moreno et al, 2011 ). In murine melanoma, the development of tumour-associated TLSs might be driven by PDPN + CAFs that are similar to LTo cells, sensitive to TNFR signalling and secrete CXCL13 ( Rodriguez et al, 2021 ). The formation of TLSs appears to crucially depend on CD4 + T-helper (Th) cells ( Box 1 ), whereas the maintenance of PDPN + fibroblasts was highly dependent on lymphotoxin in numerous disease models ( Barone et al, 2016 ; Kang et al, 2002 ; Pipi et al, 2018 ).…”