14IN - Contribution of immune response to anti-tumour effect of chemotherapy

Date 29 September 2014
Event ESMO 2014
Session Cancer immunotherapy in breast cancer: Dream or reality?
Topics Anti-Cancer Agents & Biologic Therapy
Breast Cancer, Metastatic
Cancer Immunology and Immunotherapy
Presenter Carmen Criscitiello
Citation Annals of Oncology (2014) 25 (suppl_4): iv6-iv7. 10.1093/annonc/mdu292
Authors C. Criscitiello
  • Division Of Medical Oncology, Istituto Europeo di Oncologia, 20141 - Milan/IT

Abstract

Body

Abstract:

The role of the immune system extends beyond its direct interactions with tumor cells. Complex interactions occur between the immune response and cytotoxic drugs. Some of them, such as anthracyclines and oxaliplatin, promote antitumor immunity, thus contributing to therapeutic effect by inducing immunogenic cell death, with apoptotic cancer cells emitting signals triggering antitumor immunity. Accordingly, tumor cells translocate intracellular calreticulin to the cell surface where it functions as an eat-me signal for dendritic cells (DC), thus provoking immunogenic cell death. Molecular chaperones can also be induced, appearing on the tumor cell surface where they contribute to adhesion with DC. Apoptotic tumor cells also release HMGB1, which mediates TLR4-dependent processing of the DC's phagocytic cargo and the release of maturation signals. Doxorubicin was also shown to increase tumor antigen-specific proliferation of CD8 T cells. In contrast, drugs such as cisplatin and alkylating agents lead to non-immunogenic cell death, which does not elicit an immune response and is even considered tolerogenic. Many chemotherapeutics have immunosuppressive side effects. Cyclophosphamide and methotrexate have been shown to impair T cell proliferative and/or effector functions in the periphery. However, low-dose cyclophosphamide has an immunostimulatory effect by decreasing the number and inhibitory function of CD4 + CD25+ Tregs. Metronomic cyclophosphamide suppressed Treg inhibitory functions and restored the proliferative capacity of effector T cells and NK cell cytotoxicity. Taxanes can also stimulate the antitumor immune response. The restoration of tumor antigen expression provides a rationale for investigating a possible new role for 5-FU as an immune amplifying agent in cancer patients. DCs express surface receptors which specifically recognize soluble molecules released by apoptotic tumor cells, thus playing a key role in directing their interactions with immune effectors. These receptors are either absent or affected by a loss-of-function SNP the ability of the immune system to mount an antitumor response after chemotherapy is impaired in node positive BC patients treated with anthracyclines.

Disclosure:

The author has declared no conflicts of interest.