Natural and Induced Human Antibody Response to Cancer

Fournier

et al. 2008

Intl Journal of Cancer

During melanoma progression, patients develop anti-tumor immunity including the production of anti-tumor antibodies. Although the strategies developed by malignant cells to escape anti-tumor cellular immunity have been extensively investigated, little is known about tumor resistance to humoral immunity. The main effect of IgG antibodies is to activate the immune response by binding to host Fc gamma receptors (FccR) expressed by immune cells. We previously reported in a limited study that some human metastatic melanoma cells ectopically express the FccRIIB1, an inhibitory isoform of FccR. By analyzing a large panel of different types of human primary and metastatic solid tumors, we report herein that expression of FccRIIB is restricted to melanoma and is acquired during tumor progression. We show that FccRIIB expression prevents the lysis of human metastatic melanoma cells by NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) in vitro, independently of the intracytoplasmic region of FccRIIB. Using experimental mouse models, we demonstrate that expression of FccRIIB protects B16F0 melanoma tumors from the ADCC induced by monoclonal and polyclonal anti-tumor IgG in vivo. Thus, our results identify FccRIIB as a marker of human metastatic melanoma that impairs the tumor susceptibility to FccR-dependent innate effector responses.

Section: Discussionmentioning

confidence: 68%

Selective expression of inhibitory Fcγ receptor by metastatic melanoma impairs tumor susceptibility to IgG‐dependent cellular response

Fournier

et al. 2008

Intl Journal of Cancer

“…In some patients suffering from cancer lesions, serum IgG antibodies are present that recognize cancer cells, form immune complexes and consequently activate Fc γ R. A sustained serological anti-tumor response occurs in patients with melanoma, which includes IgG antibodies against cell surface tumor antigens such as the cancer/testis antigens (NY-ESO-1, MAGE, SSX) and tyrosinase [19–21]. An indication that the serological response is beneficial comes from vaccination studies, which have demonstrated a significant association between the development of an anti-tumor antibody response and survival of melanoma patients [22–24].…”

Section: Fcγr In the Immune Systemmentioning

confidence: 99%

Metastatic Melanomas Express Inhibitory Low Affinity Fc Gamma Receptor and Escape Humoral Immunity

Dermatology Research and Practice

Fournier

et al. 2010

Our research, inspired by the pioneering works of Isaac Witz in the 1980s, established that 40% of human metastatic melanomas express ectopically inhibitory Fc gamma receptors (FcγRIIB), while they are detected on less than 5% of primary cutaneous melanoma and not on melanocytes. We demonstrated that these tumoral FcγRIIB act as decoy receptors that bind the Fc portion of antimelanoma IgG, which may prevent Fc recognition by the effector cells of the immune system and allow the metastatic melanoma to escape the humoral/natural immune response. The FcγRIIB is able to inhibit the ADCC (antibody dependent cell cytotoxicity) in vitro. Interestingly, the percentage of melanoma expressing the FcγRIIB is high (70%) in organs like the liver, which is rich in patrolling NK (natural killer) cells that exercise their antitumoral activity by ADCC. We found that this tumoral FcγRIIB is fully functional and that its inhibitory potential can be triggered depending on the specificity of the anti-tumor antibody with which it interacts. Together these observations elucidate how metastatic melanomas interact with and potentially evade humoral immunity and provide direction for the improvement of anti-melanoma monoclonal antibody therapy.

“…In many cancer types, IgG antibodies are present that recognize cancer cells, form immune complexes and therefore, activate FcγR. A sustained serological anti-tumor response occurs in patients with melanoma, which includes IgG antibodies against cell surface tumor antigens such as the cancer/testis antigens (NY-ESO-1, MAGE, SSX) and tyrosinase [10][11][12]. An indication that the serological response is beneficial comes from vaccination studies, which have demonstrated a significant association between the development of an antitumor antibody response and survival of melanoma patients [13][14][15].…”

Section: Fcγr and Immune Defenses Against Cancermentioning

confidence: 99%

“…Melanomas are known to be immunogenic and give rise to a humoral response [10][11][12]. In the human anti-tumor IgG1 and IgG3, antibodies are most likely produced and are able to interact with tumor FcγRIIB and host FcγRs.…”

Section: Fcγriib On Tumors: Friends or Foes?mentioning

confidence: 99%

Fc gamma receptors and cancer

Camilleri-Broët

et al. 2006

Springer Semin Immun

FcgammaRs are a family of heterogeneous molecules that play opposite roles in immune response and control the effector functions of IgG antibodies. In many cancers, IgG antibodies are produced that recognize cancer cells, form immune complexes and therefore, activate FcgammaR. The therapeutic efficacy of monoclonal IgG antibodies against hematopoietic and epithelial tumors also argue for an important role of IgG antibodies in anti-tumor defenses. Since the 1980s, a series of lines of evidence in experimental models and in humans strongly suggest that FcgammaR are involved in the therapeutic activity of monoclonal IgG antibodies by activating the cytotoxic activity of FcgammaR-positive cells such as NK cells, monocytes, macrophages and neutrophils and by increasing antigen presentation by dendritic cells. Since many cell types co-express activating and inhibitory FcgammaR, the FcgammaR-dependent effector functions of IgG anti-tumor antibodies are counterbalanced by the inhibitory FcgammaRIIB. In addition, some tumor cells express FcgammaR either constitutively, such as B cell lymphomas or ectopically, such as 40% of human metastatic melanoma. The tumor FcgammaR isoform is preferentially FcgammaRIIB, which is functional at least in human metastatic melanoma. This review summarizes these data and discusses how FcgammaRIIB expression may influence the anti-tumor immune reaction and how beneficial or deleterious this expression could be for the efficiency of therapeutics based on monoclonal anti-tumor antibodies.