Molecular Strategies Aimed to Boost NK Cell-based Immunotherapy of CancerSubmit Manuscript on this topic
Natural Killer (NK) cells play an essential role in the fight against cancer. In healthy humans, NK cell-mediated antitumor surveillance continually responds to the insults that drive malignant transformation of healthy cells. Tumor development is the result of a combination of deregulated molecular networks involved in promoting (i) tumor growth, (ii) tumor angiogenesis, (iii) generation and maintenance of immuno-suppressive microenvironment and (iv) evasion from innate and adaptive immune response. Consistent with this, cancer patients generally harbor dysfunctional and reduced number of effector immune cells, including NK cells. Thus, the adoptive transfer of autologous or allogeneic ex vivo activated NK cells is a promising cellular therapy for cancer that has acquired great interest in recent years.
Several pre-clinical and a few clinical trials have recently demonstrated the ability of adoptively-transferred NK cells in inhibiting and blocking tumor progression, especially in treating hematopoietic malignancies. However, these therapeutic effects in solid tumors have been scanty. Generally, adoptively-transferred NK cells are well tolerated without causing graft-versus-host disease (GvHD), an unbecoming condition that frequently occurs in cancer patients post hematopoietic stem cell transplantation (HSCT) or T cell transplantation. Although many protocols for ex vivo NK cell activation and expansion have been extensively described, the anti-cancer efficacy of adoptively-transferred NK cells needs to be improved. Thus, further investigation into the underlying molecular pathways involved in boosting the efficiency of adoptively-transferred NK cells are warranted.
Recent studies have indicated that chemotherapy and radiotherapy may function as potent immune adjuvants by promoting anti-tumor host immune activation, for example through the induction of immunogenic cytotoxic cancer cell death. In such a scenario, immunomodulatory drugs (IMiDs) enabling increased expression of ligands for NK cell-activating receptors on tumor cells would be expected to enhance tumor cell recognition by endogenous NK cells, thereby setting the stage for boosting antitumor efficacy of adoptively-transferred NK cells in the host.
NK cells also play a crucial role in monoclonal antibody-based therapies adopted for many kinds of tumors. Through the expression of FcγRIII (CD16), NK cells mediate the antibody-dependent cellular cytotoxicity (ADCC). Thus, the efficacy of monoclonal antibody-based treatment is strictly dependent on the availability of NK cells, which if compromised in cancer patients, could be overcome by the adoptive transfer of allogenic NK cells.
In solid tumors, an enhanced recruitment of NK cells to the tumor site would allow for a more robust anti-tumor immune response and could thus be clinically used towards improving patient prognosis. Recently, several agents targeting the immune checkpoint molecules (e.g. CTLA-4, LAG3, PD-1/PD-L1, ICOS, Tim-3, TIGIT) expressed on T and NK cells have been developed as a therapeutic strategy to enhance the infiltration and killing function of TILs (Tumor Infiltrating Lymphocytes). So far, pre-clinical studies have shown that antibodies against checkpoint inhibitors improve NK cell contribution to anti-tumor immune response.
In this Research Topic, we welcome the submission of Original Research, Review, and Opinion articles that highlight the recent advances in our understanding of molecular strategies aimed to boost NK cell-mediated killing of tumor cells and that provide insight into opening new viewpoints on the adoption of NK cells in cancer immunotherapy. This article collection aims to cover the following aspects towards boosting NK cell-based immunotherapy of cancer:
(i) Molecular strategies aimed at enhancing the expression of surface activating ligands on tumor cells.
(ii) Targeting molecular pathways that facilitate NK cell-mediated ADCC.
(iii) Molecular strategies that promote the production of chemoattractant molecules in the tumor microenvironment.
(iv) Molecular strategies that enhance the expression of ligands for integrins and, in general, molecules involved in the formation of activating synapse established between tumor cells and NK cells.
(v) Strategies that target immune checkpoint inhibitors, could be explored to improve the tumor susceptibility to adoptively-transferred NK cells.
(vi) Generation of chimeric receptor-engineered NK cells to be adopted for clinical treatment of cancer patients.
The combined use of molecular strategies, aimed at (i) enhancing the tumor susceptibility to NK cell killing together with those aimed at (ii) improving the efficiency of adoptively-transferred NK cells, could represent a novel approach to treat cancer, not only hematological, but also solid tumors.