Upregulation of complement proteins in lung cancer cells mediates tumor progression

Abstract

IntroductionIn vivo, cancer cells respond to signals from the tumor microenvironment resulting in changes in expression of proteins that promote tumor progression and suppress anti-tumor immunity. This study employed an orthotopic immunocompetent model of lung cancer to define pathways that are altered in cancer cells recovered from tumors compared to cells grown in culture.MethodsStudies used four murine cell lines implanted into the lungs of syngeneic mice. Cancer cells were recovered using FACS, and transcriptional changes compared to cells grown in culture were determined by RNA-seq.ResultsChanges in interferon response, antigen presentation and cytokine signaling were observed in all tumors. In addition, we observed induction of the complement pathway. We previously demonstrated that activation of complement is critical for tumor progression in this model. Complement can play both a pro-tumorigenic role through production of anaphylatoxins, and an anti-tumorigenic role by promoting complement-mediated cell killing of cancer cells. While complement proteins are produced by the liver, expression of complement proteins by cancer cells has been described. Silencing cancer cell-specific C3 inhibited tumor growth In vivo. We hypothesized that induction of complement regulatory proteins was critical for blocking the anti-tumor effects of complement activation. Silencing complement regulatory proteins also inhibited tumor growth, with different regulatory proteins acting in a cell-specific manner.DiscussionBased on these data we propose that localized induction of complement in cancer cells is a common feature of lung tumors that promotes tumor progression, with induction of complement regulatory proteins protecting cells from complement mediated-cell killing.

Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer

“…Complement activation has been implicated as a driver of tumor growth and metastasis in the tumor microenvironment. Blockade of the C3 or C5a‐C5AR1 axis was shown to impair cancer growth and bone metastasis of lung cancer in an animal model 42 , 43 . In the present study, we found that the levels of several complement factors involved in classical, lectin, and alternative pathways were enhanced in MPE.…”

Therapy‐induced senescent cancer cells exhibit complement activation and increased complement regulatory protein expression

“…An upregulation of CRP is a form of cancer immunoediting which was demonstrated in a variety of cancers including lung and breast adenocarcinomas. [60][61][62] In this context, senescent tumor cells could counteract the lethal effects of complement activation by upregulating CD59 to inhibit C5b-9-mediated lysis. In addition, increased production of CFH is expected to modulate complement both in an autocrine and in a paracrine manner, because other cells in the tumor microenvironment would be protected from complement activation through the binding of CFH to their surfaces.…”

“…63 While C3 in circulation is mostly produced by the liver, a recent study showed that C3 produced locally by tumor cells can mediate tumor progression. 60 Nevertheless, it should be noted that the SASP is immensely versatile and is partly dependent on the type of the senescence trigger and the genetic background of the cell. For example, MCF7 cells did not upregulate C3 expression in a similar manner to A549 cells despite both cell lines undergoing senescence in response to chemotherapy.…”

“…More specifically, CFH is a secreted CRP that recognizes host cell surfaces and inhibits the alternative pathway C3 convertase formation, while CD59 is a cell‐bound CRP that is the main inhibitor of C5b‐9 formation. An upregulation of CRP is a form of cancer immunoediting which was demonstrated in a variety of cancers including lung and breast adenocarcinomas 60–62 . In this context, senescent tumor cells could counteract the lethal effects of complement activation by upregulating CD59 to inhibit C5b‐9–mediated lysis.…”

“…C3 is central to the function of complement and is the point of convergence of the three complement activation pathways, as its cleavage produces the anaphylatoxin C3a, the opsonin C3b and the convertases needed to propagate complement activation 63 . While C3 in circulation is mostly produced by the liver, a recent study showed that C3 produced locally by tumor cells can mediate tumor progression 60 . Nevertheless, it should be noted that the SASP is immensely versatile and is partly dependent on the type of the senescence trigger and the genetic background of the cell.…”