Integrated genomic and transcriptomic analysis reveals unique characteristics of hepatic metastases and pro-metastatic role of complement C1q in pancreatic ductal adenocarcinoma

Despite the advances in our understanding of the genetic and immunological basis of cancer, cancer remains a major public health burden with an ever-increasing incidence rate globally. Nevertheless, increasing evidence suggests that the components of the complement system could regulate the tumor microenvironment (TME) to promote cancer progression, recurrence, and metastasis. In the present study, we used an integrative multi-omics analysis of clinical data to explore the relationships between the expression levels of and genetic and epigenetic alterations in C3, C5, C3AR1, and C5AR1 and tumor immune evasion, therapy response, and patient prognosis in various cancer types. We found that the complements C3, C5, C3AR1, and C5AR1 have deregulated expression in human malignancies and are associated with activation of immune-related oncogenic processes and poor prognosis of cancer patients. Furthermore, we found that the increased expression levels of C3, C5, C3AR1, and C5AR1 were primarily predicted by copy number variation and gene methylation and were associated with dysfunctional T-cell phenotypes. Single nucleotide variation in the gene signature co-occurred with multiple oncogenic mutations and is associated with the progression of onco-immune-related diseases. Further correlation analysis revealed that C3, C5, C3AR1, and C5AR1 were associated with tumor immune evasion via dysfunctional T-cell phenotypes with a lesser contribution of T-cell exclusion. Lastly, we also demonstrated that the expression levels of C3, C5, C3AR1, and C5AR1 were associated with context-dependent chemotherapy, lymphocyte-mediated tumor killing, and immunotherapy outcomes in different cancer types. In conclusion, the complement components C3, C5, C3AR1, and C5AR1 serve as attractive targets for strategizing cancer immunotherapy and response follow-up.

Section: Discussionsupporting

confidence: 88%

Pan-Cancer Analysis of Immune Complement Signature C3/C5/C3AR1/C5AR1 in Association with Tumor Immune Evasion and Therapy Resistance

Lawal

Tseng

Olugbodi

et al. 2021

“…This mechanism, possibly important for effective immune response, may play a key role in pNETs and highlight potential therapeutic targets to invigorate efficient immune response. Recently, Yang et al reported compelling results about the potential involvement of the complement C1q activation in liver metastasis of patients with pancreatic adenocarcinomas [ 54 ]. Moreover, they showed that C1q is mainly expressed at tumor stroma rather in tumor cells and is involved in complement cascade.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Neutrophils in Metastatic Evolution of Pancreatic Neuroendocrine Tumors

Debien

Davidson

Baltzinger

et al. 2021

Well-differentiated pancreatic neuroendocrine tumors (pNET) have an unpredictable natural history. The identification of both blood and tumor immune features associated with patients’ outcomes remains limited. Herein, we evaluated the best prognostic value of the neutrophils-to-lymphocyte ratio (NLR) in a cohort of 144 pNETs. The NLR ≥ 4 was associated with worse overall survival in both univariate analysis (HR = 3.53, CI95% = 1.50–8.31, p = 0.004) and multivariate analysis (HR = 2.57, CI95% = 1.061–6.216, p = 0.036). The presence of synchronous liver metastasis was identified as a prognostic factor in multivariate analysis (HR = 3.35, CI95% = 1.411–7.973, p = 0.006). Interestingly, the absolute tumor-associated neutrophils count was higher in liver metastasis as compared to their paired primary tumor (p = 0.048). Deconvolution of immune cells from the transcriptome of 83 primary tumors and 30 liver metastases reveals enrichment for neutrophils in metastasis relative to primary tumors (p = 0.005), and this was associated with upregulation of the complement pathway (NES = 1.84, p < 0.0001). Combining neutrophils signature and complement pathway genes, unsupervised clustering identified two pNETs subgroups, namely Neu-Comp1 and Neu-Comp2. Characterized by neutrophils infiltration and activation of the complement pathway, Neu-Comp1 was highly enriched for metastatic liver samples as compared to Neu-Comp2 (p < 0.0001). These data suggest the possible link between liver metastasis, complement pathway activation, and neutrophils infiltration in well-differentiated pNET and open avenues for targeting complement pathways in these tumors.

“…In a KRAS-mutated murine PDAC cell model, tumor-intrinsic CXCL1 expression alone determines the quantitative and qualitative features of infiltrative CD8 + T cells and hence response to checkpoint immunotherapy [41]. In addition, after successfully metastasizing to a distant organ, PDAC cells establish a new TME that is remarkably similar to the primary tumor, featuring a highly fibrotic stroma, heavy infiltration of suppressive myeloid cells, and exclusion of cytotoxic T cells [42,43]. The intense desmoplastic histologic feature is not a cardinal feature of other KRAS-mutant cancer types such as non-small cell lung cancer (NSCLC), colorectal cancer, (CRC) or multiple myeloma.…”

Section: Forward Circuitry: Oncogenic Kras Drives Inflammatory Cytokines To Shape the Tmementioning

confidence: 99%

Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities

Bansod

Dodhiawala

Lim

2021

Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.