Chemotherapy‐induced differential changes in lymphocyte subsets and natural‐killer‐cell function in patients with advanced breast cancer

Sewell, H. F.; Halbert, C F; Robins, R. A.; Galvin, A; Chan, Stefanie; Blamey, R. W.

doi:10.1002/ijc.2910550506

Cited by 47 publications

(30 citation statements)

References 14 publications

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“…Mackall reported on the immunosuppressive effects of cytotoxic CT, such as a decrease in total T lymphocytes and the CD4 + subset following adjuvant CT and radiotherapy for breast cancer and the slow recovery of CD3 -/CD4 + lymphocytes in patients treated with intensive CT (2). Significant reductions in the absolute number of CD4 + lymphocytes were also reported by Sewell et al (9) in breast cancer patients treated with standard CT and by Sara et al (10) in patients with solid tumours treated with CT. Schroeder and colleagues (11) reported specific alterations of the T cell population in patients with breast cancer, such as a significant reduction in the absolute T cell number, but not in the CD4 + /CD8 + ratio and a significant increase in CD3 + T cells. In contrast with such aberrations of PBL reported in patients submitted to cytotoxic CT, Melichar et al (12) observed only a few distinct PBL changes in a population of breast cancer patients and suggested the presence of T-cell Table II.…”

Section: Discussionsupporting

confidence: 67%

Effect of peg-filgrastim-supported dose-dense adjuvant chemotherapy on the peripheral blood leukocyte phenotype in breast cancer patients

et al. 2008

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Abstract. The aim of this study was to evaluate the effect of dose-dense adjuvant chemotherapy regimens with pegfilgrastim support on the phenotype of peripheral blood leukocytes in breast cancer patients. We evaluated the leukocyte phenotype of 14 patients aged 46-67 years undergoing 4 courses of chemotherapy with either epirubucin/ cyclophosphamide (n=7) or 5-fluorouracil/epirubucin/ cyclophosphamide (n=7) followed by 4 courses of taxol supported by peg-filgrastim (6 mg) administered 72 h after each chemotherapy course. The overall leukocyte number significantly increased from the first treatment course, while total lymphocytes tended to decrease with a negative peak following the 6th course (p=0.03). B (CD19 + , CD20 + ) and early B lymphocyte subsets (CD20 + /CD38 + ) significantly decreased during treatment (p<0.05), while T lymphocyte subsets did not show significant changes, except a decrease in T helper (CD4 + ) cells. Immature T lymphocytes (CD4 + / CD8 + subset), dendritic cells (CD11c + ) and NK cells (CD56 + ) increased with respect to the baseline. Our results suggest that dose-dense chemotherapy programs with the support of pegfilgrastim did not significantly impair the immune system of breast cancer patients and allowed for a rapid restoration of most immune competent cells. These observations may have important clinical implications with a view to vaccination or other immunotherapeutic approaches to solid tumours.

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Section: Discussionsupporting

confidence: 67%

Effect of peg-filgrastim-supported dose-dense adjuvant chemotherapy on the peripheral blood leukocyte phenotype in breast cancer patients

et al. 2008

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“…Several studies in humans have shown that among lymphocyte subsets, B cells are the cells most affected by chemotherapy, followed by CD4 ϩ T cells, with CD8 ϩ T cells remaining relatively well preserved. [41][42][43][44] Interestingly, the remaining clonogenic T lymphocytes derived from acute leukemia patients with therapy-induced leukopenia have shown a broad cytokine response to in vitro activation. 45 We have previously shown in the SJL AML model that absolute peripheral lymphocyte numbers return to normal within a week after chemotherapy with cytarabine and doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

The combination of chemotherapy and systemic immunotherapy with soluble B7–immunoglobulin G leads to cure of murine leukemia and lymphoma and demonstration of tumor-specific memory responses

Runyon¹,

Lee²,

Zuberek³

et al. 2001

Blood

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Major mechanisms underlying poor immune responses to autologous tumorassociated antigens are overwhelming tumor kinetics and the absence of effective T-cell costimulation by antigen-presenting cells. To address these issues, leukemia and lymphoma mice were treated with the combination of chemotherapy and systemic immunotherapy with recombinant soluble murine B7-immunoglobulin G (IgG) molecules. In this report, 3 murine models were used, a radiationinduced SJL acute myeloid leukemia, a transplantable spontaneous SJL lymphoma, and the C57BL/6 EL-4 thymic lymphoma. Various treatment modalities were evaluated: single treatments with either B7-IgG or chemotherapy as well as combination therapies. The results demonstrate the following: (1) in all tumor models, the combination of chemotherapy and soluble B7-IgGs is more potent than either therapy alone, leading to cure of tumorbearing animals; (2) the therapeutic responses are T-cell-dependent, because combined therapy is not efficacious in severe combined immunodeficient mice; (3) the rejection of tumor cells leads to the development of tumor-specific immunity, because cured mice are immune to the rejected tumor but not to a different syngeneic tumor; and (4) 51 IntroductionMajor recent discoveries that have drastically modified the nature of T-cell-directed immunotherapy in cancer are the cloning of several tumor-associated antigens (TAAs) that elicit autologous cytotoxic T-cell responses 1,2 and the discovery of new molecules and pathways involved in T-cell activation and costimulation. 3,4 This knowledge has guided the design of numerous preclinical and clinical studies that, in turn, have generated remarkable insight into the mechanisms controlling host responses to cancer cells. Thus, it is now accepted that few spontaneous tumors are immunogenic, but most, if not all, are antigenic. 5,6 However, what ultimately determines the outcome of an endogenous antigen encounter is the context in which that particular antigen is presented to T cells. 7,8 In the absence of danger signals that accompany tissue destruction and inflammation (typically observed during viral infection), the outcome is immune ignorance. 9,10 At the level of antigenpresenting cell (APC)-T-cell interactions, the local danger signals translate primarily into the up-regulation of T-cell costimulatory signals provided by APCs at the time of antigen presentation.Costimulation is defined as a signal necessary for optimal T-cell activation and survival delivered to T cells along with the T-cell receptor (TCR) signal, provided by APCs, ie, activated B cells, macrophages, and dendritic cells. 11,12 Over the years, the CD28/B7 T-cell costimulatory pathway has emerged as the key regulator of T-cell responses. The signal involves the interaction of the T-cell surface antigen CD28 with the members of the B7 family molecules B7.1 (CD80) and B7.2 (CD86) expressed on APCs. 13,14 Following a TCR-mediated signal, ligation of CD28 results in up-regulation of the interleukin 2 (IL-2)-receptor, increased IL-2 messe...

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“…2,3 In breast cancer patients with localized and metastatic disease, cytotoxic drug regimens were shown to induce an overall impairment of NK-cell responses. 4,5 Recently, a metronomic (that is, low dosage for a prolonged period of time) cyclophosphamide (CTX) regimen was shown to potently stimulate NK-dependent antitumor immunity in end-stage cancer patients 6 and the prompt recruitment of DCs, macrophages and NK cells to the tumor site in diverse mouse models. 7,8 Interestingly, combined treatment with 5-Fluorouracil (5-FU) and IFN-a resulted in higher numbers of infiltrating NK cells with enhanced cytotoxicity in a pancreatic tumor model.…”

Section: Effects On the Innate Immune Systemmentioning

confidence: 99%

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

et al. 2013

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Conventional anticancer chemotherapy has been historically thought to act through direct killing of tumor cells. This concept stems from the fact that cytotoxic drugs interfere with DNA synthesis and replication. Accumulating evidence, however, indicates that the antitumor activities of chemotherapy also rely on several off-target effects, especially directed to the host immune system, that cooperate for successful tumor eradication. Chemotherapeutic agents stimulate both the innate and adaptive arms of the immune system through several modalities: (i) by promoting specific rearrangements on dying tumor cells, which render them visible to the immune system; (ii) by influencing the homeostasis of the hematopoietic compartment through transient lymphodepletion followed by rebound replenishment of immune cell pools; (iii) by subverting tumor-induced immunosuppressive mechanisms and (iv) by exerting direct or indirect stimulatory effects on immune effectors. Among the indirect ways of immune cell stimulation, some cytotoxic drugs have been shown to induce an immunogenic type of cell death in tumor cells, resulting in the emission of specific signals that trigger phagocytosis of cell debris and promote the maturation of dendritic cells, ultimately resulting in the induction of potent antitumor responses. Here, we provide an extensive overview of the multiple immune-based mechanisms exploited by the most commonly employed cytotoxic drugs, with the final aim of identifying prerequisites for optimal combination with immunotherapy strategies for the development of more effective treatments against cancer.

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Chemotherapy‐induced differential changes in lymphocyte subsets and natural‐killer‐cell function in patients with advanced breast cancer

Cited by 47 publications

References 14 publications

Effect of peg-filgrastim-supported dose-dense adjuvant chemotherapy on the peripheral blood leukocyte phenotype in breast cancer patients

Effect of peg-filgrastim-supported dose-dense adjuvant chemotherapy on the peripheral blood leukocyte phenotype in breast cancer patients

The combination of chemotherapy and systemic immunotherapy with soluble B7–immunoglobulin G leads to cure of murine leukemia and lymphoma and demonstration of tumor-specific memory responses

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

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