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

Bashir Lawal,Mohamed Mahmoud,Sitthichai Iamsaard,Sung-Hui Tseng,Janet Olugbodi,Gaber Batiha,Sahar Ahmed,Omotayo Ilesanmi,Alexander Wu

doi:10.3390/cancers13164124

Abstract

Simple SummaryWe used multi-omics approaches to evaluate the association of complement signature C3/C5/C3AR1/C5AR1 with tumor immune phenotypes and prognosis across various cancer types. We found that the gene signatures have deregulated expression in human malignancies and demonstrated context-dependent association with tumor immune evasion, prognosis, and therapy response across the various cancer types. Further 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. The complement components C3, C5, C3AR1, and C5AR1 serve as attractive targets for strategizing cancer immunotherapy and response follow-up.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.

Highlights

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 [1]
Our results indicate that C3 is downregulated in BLCA, BRCA, CHOL, COAD, LIHC, LUAD, LUSC, PRAD, and READ but upregulated in KIRC, KIRP, SKCM metastasis, STAD, and THCA; C5 is downregulated in BLCA, BRCA, CHOL, ESCA, KICH, KIRC, KIRP, LIHC, LUAD, LUSC, SKCM, THCA, and UCEC but upregulated in COAD and HNSC-HPVpos; C5AR1 is downregulated in BLCA, LIHC, LUAD, and LUSC but upregulated in CHOL, ESCA, HNSC, KIRC, KIRP, SKCM metastasis, and STAD; and C3AR1 is downregulated in COAD, LUAD, LUSC, and READ but upregulated in ESCA, HNSC-HPVpos, HNSC, KIRC, KIRP, CHOL, SKCM, STAD, and THCA when compared with the adjacent normal tissue (Figure 1A)
We found that higher expression levels of C3 in COAD, GBM, KIRC, LGG, and LUSC; C3AR1 in GBM, LGG, and COAD; C5 in COAD, KICH, STAD, and UVM; and C5AR1 in THCA tumors are associated with a shorter survival duration of the cohorts

Summary

Introduction

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 [1]. The complement system is classified into seven functional components: initiator complement components (e.g., the C1q complex, mannose-binding lectin (MBL)); enzymatic mediators (e.g., C1r, C1s, MASP2, and factor B, C3, and C5 convertases); membranebinding components (e.g., C3b and C4b); inflammatory mediators: (e.g., C3a, C5a, and C4a); membrane attack proteins (e.g., C5b, C6, C7, C8, and C9); complement receptor proteins (e.g., CR1, C3aR1, and C5aR1); and regulatory complement components (e.g., factor I, factor H, CD59, and CD46). These proteins of the complement system are primarily in an inactivated form and are activated by a series of chain reaction pathways, the classical, lectin, and alternative pathways, which activate the complement components in sequential order. Inappropriate complement activations and dysregulation of the immune regulatory function of complements have been implicated in the development and progression of numerous inflammatory, degenerative, and autoimmune diseases [5,6,7,8]

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