Is There an Opportunity for Current Chemotherapeutics to Up-regulate MIC-A/B Ligands?

Abstract

Natural killer (NK) cells are critical effectors of the immune system. NK cells recognize unhealthy cells by specific ligands [e.g., MHC- class I chain related protein A or B (MIC-A/B)] for further elimination by cytotoxicity. Paradoxically, cancer cells down-regulate MIC-A/B and evade NK cell’s anticancer activity. Recent data indicate that cellular-stress induces MIC-A/B, leading to enhanced sensitivity of cancer cells to NK cell-mediated cytotoxicity. In this Perspective article, we hypothesize that current chemotherapeutics at sub-lethal, non-toxic dose may promote cellular-stress and up-regulate the expression of MIC-A/B ligands to augment cancer’s sensitivity to NK cell-mediated cytotoxicity. Preliminary data from two human breast cancer cell lines, MDA-MB-231 and T47D treated with clinically relevant therapeutics such as doxorubicin, paclitaxel and methotrexate support the hypothesis. The goal of this Perspective is to underscore the prospects of current chemotherapeutics in NK cell immunotherapy, and discuss potential challenges and opportunities to improve cancer therapy.

Cytotoxic Immunity in Peripheral Nerve Injury and Pain

“…Vincristine and oxaliplatin themselves only mildly impair NK cell cytotoxicity (Markasz et al, 2007). Chemotherapeutic agents can also enhance NK cell function by down-regulation of inhibitory 'self ' ligands on the target cell surface (Fine et al, 2010); therefore the sensitivity of tumor or other target cells to NK cell cytotoxicity can be initiated by modulation of activating and inhibitory ligands (Quirk and Ganapathy-Kanniappan, 2017). Pre-treatment with the cytokine interleukin 2 (IL-2) increases the anti-tumor response rate to oxaliplatin particularly in patients with low blood lymphocyte counts (Lissoni et al, 2005) but there are currently no data available on how this immune modulation may impact on the neuropathic side effects of chemotherapy.…”