| Summary: | 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 <i>C3</i>, <i>C5</i>, <i>C3AR1</i>, and <i>C5AR1</i> and tumor immune evasion, therapy response, and patient prognosis in various cancer types. We found that the complements <i>C3</i>, <i>C5</i>, <i>C3AR1</i>, and <i>C5AR1</i> 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 <i>C3</i>, <i>C5</i>, <i>C3AR1</i>, and <i>C5AR1</i> 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 <i>C3</i>, <i>C5</i>, <i>C3AR1</i>, and <i>C5AR1</i> 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 <i>C3</i>, <i>C5</i>, <i>C3AR1</i>, and <i>C5AR1</i> were associated with context-dependent chemotherapy, lymphocyte-mediated tumor killing, and immunotherapy outcomes in different cancer types. In conclusion, the complement components <i>C3</i>, <i>C5</i>, <i>C3AR1</i>, and <i>C5AR1</i> serve as attractive targets for strategizing cancer immunotherapy and response follow-up.
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