Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines

Abstract

Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4 þ and CD8 þ T cells producing interferon-c. In many instances, cancer progression is associated with high titers of tumor-specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-celldepleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas.

Killing cancer cells, twice with one shot

“…Hannani et al 15 show that while the activity of CD4 and CD8 T cells is important for ICD, as previously known, the activity of B cells and the humoral arm of the adaptive immune system is not. Little anti-cancer and anti-calreticulin antibodies are produced following ICD, and their relevance for the anti-tumor response appears minimal.…”

“…Cells can be severely stressed because of an inhospitable environment or condition, or because of tissue injury; they can also be hit by radiotherapy or chemotherapy, which create stress on their own. Cancer cells will eventually die because of treatment, but only if they undergo ICD they will arouse and instruct the adaptive immune system (or, rather, the cellular branch of the adaptive immune system) 15 against their kin. ICD requires the concomitant release of high-mobility group box 1 protein (HMGB1) and of ATP into the extracellular space, and the exposure of calreticulin (CRT) on the cell surface.…”

Anti-tumor immunity of BAM-SiPc-mediated vascular photodynamic therapy in a BALB/c mouse model

“…These observations agree with those reported for WST11-VPDT but differ from the results of immunogenic chemotherapy using anthracycline, in which no tumor-specific antibodies could be boosted. 13,62 The serum of VPDT-cured mice, with no detectable IFN-c or TNF-a (analyzed by ELISA, n 5 10, data not shown), possessed anti-tumor properties that were T-cell-dependent (Figure 6c). These results are generally consistent with those reported in other studies.…”

“…In chemotherapy, the activity of B cells has been reported to strengthen resistance to the treatment of tumors in nude mice with anthracycline or oxaliplatin. 62,63 Nevertheless, there is accumulating evidence suggesting that tumor-infiltrating B cells are anti-tumor in nature because they can (i) exert direct cytotoxicity on tumor cells via TRAIL signaling, (ii) assist cellmediated immunity with Th1 cytokine secretion, (iii) assist presentation of antigens to T cells via membrane-bound Ig molecules, and (iv) produce tumor-reactive antibodies. [64][65][66] Tumor-reactive antibodies could, indeed, trigger anti-tumor immunity in vivo.…”

Trial Watch: Peptide-based anticancer vaccines

“…[56][57][58][59] Although the importance of humoral immunity in anticancer immunosurveillance is being reconsidered, [60][61][62] tumor-targeting humoral responses developing in a therapeutic setting are generally insufficient to mediate tumor rejection. [63][64][65][66] Thus, anticancer vaccines must elicit cellular responses that are (1) specific for an endogenous (and in some cases potentially cross-reactive) antigen; (2) sufficiently intense to mediate robust cytotoxic effects against malignant cells; and (3) sufficiently broad to overcome the intrinsic heterogeneity of neoplastic cells and mediate tumor eradication rather than immunoediting only. Several approaches have been developed to ameliorate the ability of TAAs and peptides thereof to elicit therapeutically relevant anticancer immune responses.…”