tumor and immunity

Journal reading

Changes in host defence induced by malignancies and

antineoplastic treatment: implication for

immunotherapeutic strategies97/11/26 R2 林軒名

Content

• Introduction• Barriers• Adaptive immunity• Cytokines

Immunity

Malignancy Therapy

Introduction

Barriers

• The exterior bodily defences : Mucosa• Mucositis increases the risk for infections• Current therapy: essentially palliative• Palifermin (recombinant keratinocyte

growth factor, fibroblast growth factor 7), interleukin-11, interleukin-15, and granulocyte-macrophage colony-stimulating factor

Innate immunity ： NK cells

• Deficiencies • severe infection with viral and mycobacterial pathogens.

• Maintaining continuous remission for acute leukemia.

• Thymoma and melanoma cells, can interrupt functional maturation of natural killer cells.

• Aggressive cytotoxic regimens decrease the number of circulating natural killer cells

Innate immunity ： NK cells

• In Rat, ketamine, thiopental, and morphine, suppress naturalkiller-cell activity

• Hyperthermia increases NK cells• Natural-killer-cell-based

immunotherapeutic strategies include the proliferation and activation of the cells in vivo and the combination of the cells with other treatment modalities, for example with bispecific antibodies.

Innate immunity ： Phagocytes

• key effector cells with microbicidal capabilities.

• febrile neutropenic: risk-adapted approach o Expected duration and depth of neutropenia,o the type of underlying Malignancyo Clinical parameterso Laboratory markers such as interleukin-6

• Qualitative defects of phagocytic function • increase the risk for infection


• GlucocorticosteroidsoDownregulate NADPH-oxidase systemosuppress the production of various

cytokines by several mechanisms, inhibition of the transcription factor nuclear factor κB(NFκB)

oFluorouracil, doxorubicin, and cyclophosphamide, or interleukin-2, suppressneutrophil migration


• Etoposide: induces proinflammatory cytokine production

• Rituximab: Induces a depletion of B cells,• Morphine: suppresses complement and

Fcγ-receptor expression and neutrophil functions

• G-CSF: primary prophylaxis for chemotherapy-induced febrile neutropenia:

• Granulocyte transfusions: no defined benefit.

Innate immunity ： Dendritic cells

• Antigen-presenting cells• Initiate adaptive immune responses by

secreting cytokines and activating lymphocytes

• Effect o Number reduced: ALL or non-small-cell lung

cancer (NSCLC)o Functional impairment: Chemo therapy for

malignancy

Olivera J. Finn, Ph.D. Cancer Immunology, N Engl J Med 2008;358:2704-15


• Imatinib o inhibitor of tyrosine kinases o inhibits differentiation of CD34+ progenitors

into dendritic cells as well as the function of dendritic cells and monocytes


• Dendritic cells pulsed with pathogen or tumour-derived antigen(s)o Example: aspergillosis, papillomavirus

• Imiquimod (synthetic agonist of Toll-like receptor 7), are directly involved in the destruction of basal cell carcinoma • bladder cancer.

Adaptive immunity: T cells

• Regulatory T cells: o Suppression of both adaptive and innate

immunity thus preventing autoimmunity and allograft rejection, and downregulating antimicrobial and antitumour immune responses

o TReg cells depend on exogenous interleukin 2

• CD4+ and CD8+ T cells: increase the host response against microorganisms


• Rapid recovery of T cells after treatment for malignancy is associated with a better prognosis

• Chronic graft-versus-host-disease have a lower incidence of relapse

• Depletion of the TReg subset : augment antitumour immunity


• Myeloid malignancies or Hodgkin’s diseaseo suppressed Cell-mediated immunityo increased numbers of TReg cellso Ex: lower expression of the T-cell receptor

(TCR)-zeta chain in Hodgkin’s disease; Myeloma: multiple signalling defects of T cells


• Cyclophosphamide: induce a profound reduction in the number of circulating TReg cells

• Interleukin-2: increased number TReg cells, suppressive activity in vitro. No postive results.

• Temozolomide: CD4+ lymphopenia. Induced Pneumocystis jiroveci and Aspergillus


• Alemtuzumab• Imatinib mesylate• Radiotherapy: lymphocyte

subpopulations• Whole-body hyperthermia: decreases

peripheral numbers of T cells• Amphotericin B: negatively affect the• cytotoxic T-cell function in vivo

• ALLo defects in CD4+ and CD8+ T-cell numbers

• Donor-derived T cells (after alloPBSCT) beneficial in patients with severe viral or fungal infection or in patients with relapse of the underlying malignancy

• Donor lymphocyte infusionseffective, but high risk of graft versus host disease

Adaptive immunity: Humoral defence mechanisms

Cytokines

Olivera J. Finn, Ph.D. Cancer Immunology, N Engl J Med 2008;358:2704-15

Reference

• Olivera J. Finn, Ph.D. Cancer Immunology, N Engl J Med 2008;358:2704-15.

• Mark J. Smyth, Ph.D. Imatinib Mesylate : Uncovering a Fast Track to Adaptive Immunity NEJM 354;21 May 25, 2006

• Glenn Dranoff, Cytokines in cancer pathogenesis and cancer therapy Nature Reviews Cancer 4, 11 - 22 (01 Jan 2004), doi: 10.1038/nrc1252, Review

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