Novel entities expressed on the surfaces of tumor cells have long been known to activate all three pathways of the complement system. Nevertheless, complement activation, even with interventional tumor specific complement activating antibodies, does not generally lead to tumor elimination, or even control of its progression. Conventionally, this has been ascribed to the tumor cell’s anti-complement protective mechanisms,  the most prominent of which is the increased expression of the membrane complement regulators CD46, CD55, and CD59 on the tumor cells relative to the surrounding normal tissue. Indeed, in human tumor xenograft mouse model systems, combinations of anti-tumor antibody with blocking membrane complement regulatory protein antibodies were in some cases shown to be effective in promoting the survival of the animal, although to be translatable to humans, approaches such as the use of bispecific antibodies, with one Fab directed against the tumor-specific antigen and the other directed against the membrane complement regulator, would likely be necessary to not cause complement dysregulation on normal tis sue (reviewed in Gancz and Fishelson ). However, in the absence of such complement regulatory protein-targeted interventions, far from complement activation just being ineffective in eliminating tumor progression, over the past decade a compelling picture has emerged that tumor-associated complement activation leads to an immunosuppressive state in the tumor’s microenvironment and results in an attenuations of the tumor-specific cytotoxic T-cell responses. As reviewed by Pio et al. and Kolev and Markiewski, the mechanisms underlying this observation are both varied and complex. Although a full discussion of these would be beyond the scope of this chapter, we would like to briefly highlight what is probably the most prevalent and best characterized of the mechanisms, as it is also a potential therapeutic target. Specifically, it involves the C5a:C5aR1 axis in recruiting C5aR1-bearing myeloid-derived suppressor cells (MDSC) to the site of the tumor through the chemotactic activity of C5a. Beyond just acting as a chemotaxis receptor, binding of C5a to the MDSC results in signal-mediated metabolic changes leading to the synthesis and secretion of both reactive oxygen and reactive nitro gen species, both of which inhibit antigen-specific responses in CD8 + T cells. Other effects of C5a-activated MDSC in the tumor microenvironment include the production of immunosuppressive cytokines (e.g., TGF- β 1 and IL-10) leading to the accumulation of Tregs and changes in CD4 + T-cell polarization from the anti-tumor Th1 phenotype to the tumor-promoting Th2 phenotype. C5aR1 signaling also affects macrophages in the tumor environment by causing a change from the pro-inflammatory M1 phenotype to the immunosuppressive, and therefore tumor-promoting, M2 phenotype.

Despite the emergence of T-cell checkpoint inhibitor-based immunotherapy, i.e., anti-PD-1 on the T cell, or anti-PD-L1 on the tumor cell, as a potent tool in the treatment of several cancer types, including melanoma, non-small cell lung cancer, kidney cancer, colon cancer, and Hodgkin lymphoma, many patients either are or become resistant to this monotherapy and some cancer types do not respond at all. Given the above described importance of the C5a:C5aR1 axis in promoting a T-cell immunosuppressive state in the tumor micro environment, a combination therapy targeting both the PD-1:PD-L1 and C5a:C5aR1 axes has been evaluated in preclinical models of lung cancer, melanoma, and colon cancer. Relative to each mono therapy, the combined immunotherapy showed synergistic effects in the reduction of both tumor growth and metastatic progression that correlated with an increase in CD8 + T cells and a decrease in the number, or inhibitory activity, of MDSC at the site of the tumor. Based on these preclinical findings, there is an ongoing human phase I/II clinical trial (STELLAR-001, Innate Pharma, and MedImmune) in which the anti-PD-L1 therapeutic antibody durvalumab is being evaluated in combination with an anti-C5aR1 monoclonal (IPH5401) in patients having advanced solid tumors, including non-small cell lung

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم صناعة الشبابيك يشرع بإدامة شباكين قديمين لمرقد الإمامين العسكريين (عليهما السلام)

فرقة العباس (عليه السلام) تختتم خدماتها المقدمة للزائرين في سامراء

موكب العتبتين المقدستين يحيي ذكرى استشهاد الإمام الهادي (عليه السلام) في سامراء

العتبة العسكرية المقدسة تكرّم وفد العتبة العباسية المقدسة لمشاركته في تقديم الخدمات للزائرين

المزيد

الآخبار الصحية

كنز غذائي على طبقك.. ماذا تفعل السبانخ بجسمك؟

ما لا يتوقعه أحد.. "سر غذائي" في الجبن الدسم

لتحسين الهضم والنوم.. هذا أفضل وقت لتناول العشاء

10 طرق بسيطة وغير مألوفة لحرق المزيد من السعرات يوميا

المزيد

الآخبار التكنلوجية

سابقة بعالم الطيران.. طائرة تقرر الهبوط بنفسها بعد ظرف طارئ

"الإنفلونزا الخارقة" تكتسح دول العالم.. وتثير قلقا كبيرا

مرحلة ما قبل الأعراض.. دواء جديد يستهدف "شرارة" الزهايمر

إزالة ثاني أكسيد الكربون من الغلاف الجوي.. ما دور المحيطات والبحار؟

المزيد

مواضيع ذات صلة

Complement and T-Cell Immunity

Focusing Antigen on Follicular Dendritic Cells

B-Lymphocyte Coreceptors

The Complement System : Alternative Pathway

The Complement System : Lectin Pathway

The Complement System: Classical Pathway

Secondary Lymphoid Tissue

The Hematopoietic Microenvironment

The Pro-B- and Pre-B-Cell Checkpoints

Immunoglobulin Gene Rearrangement : Heavy Chain Gene Rearrangement

Transcriptional Regulation of B-Cell Development

Stages of B-Cell development