New insights into Innate Immune cell-based immunotherapies in cancer

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Background

Immunotherapeutic strategies are aimed to inhibit or potentiate directly adaptive or innate immune responses. Immunomodulatory approaches on adaptive immune response have shown some success in clinic assays with promising therapeutic potential, but have some limitations related to their tumor-dependent effectiveness. The frequency of functional cytotoxic T cells is often very low due to tumor mutations or tumor resistance mechanisms which impaired T-cell infiltration in tumors, appropriate recognition of peptide-MHC class I complexes on tumor cells and downregulation of co-stimulatory molecules. Indeed, tumors need to present a high mutational load to be sensitive to adaptive immunotherapy. Additionally, the adaptive immunotherapy failure is also orchestrated by the tumor microenvironment (TME) and notably the innate immune component, sustaining an immune tolerance and a T cell exclusion or exhaustion. The innate immune system can inhibit tumor progression directly or indirectly by recruiting adaptive immune cells but can also have a central role in cancer development and progression, both through remodelling of the TME and establishment of an immunosuppressive environment. Recently, an interest on targeting innate immune cells has therefore emerged, regarding their high plasticity, their potent and extremely rapid response, and their ability to influence the outcome of the adaptive immune response.

In the last years, the importance of targeting innate immune cells is recognized by the increasing number of clinical trials for cancer.

One of the main advantages of immunotherapy is that it works in some malignancies that are refractory to chemotherapy and radiotherapy, often due to a permissive TME shaped by the innate immune component. The goal is therefore to target these innate immune cells to weaken the tumor, activating them for anticancer responses or inactivate them in case of suppressive functions and/or pro-tumor effects.

Some interesting approaches begin to be developed such as the application of CAR technology to NK cells, γδ cells, and macrophages. All this evidence highlights the necessity to develop holistic approaches capable of dissecting the contribution and interplay of the different immune components of the TME.

Further understanding of the contribution of the innate immune compartments to anticancer adaptive immune response will be a key aspect to explore new treatments or combinatorial therapeutic strategies with connections between innate and adaptive immune cells.

However, even innate immune compartments have a high impact on tumor evolution, and can also be influenced by external events such as gender, age, external/social environment, and childhood diseases.

These questions can also be addressed to understand the failures of immunotherapies and perhaps take them into account in future therapeutic strategies.

This Research Topic aims to present recent advances and novel insights into the innate immune cells based immunotherapies with a special interest in NK, iNKT, MAIT, iLC,  T lymphocytes, macrophages, and dendritic cells. New methods targeting these cells but also impact of external events on their responses have to be discussed in this collection.

The final goal of this articles collection is to help link bench to bedside research on cancer, with the final aim of promoting novel tailored therapeutic approaches.



This Research Topic calls for Original Research, Review, Clinical Trial, and Perspective articles focusing on, but not limited to, the following subtopics related to:

• Engineering innate immune cells such as CAR NK, CAR macrophages, CAR  T cells….

• Targeting innate immune cells with antibodies, bispecific γδ T cell or NK Cell Engagers, molecules, nanotools….

• Impact of gender and age on anticancer responses of innate immune cells

• Impact of medical history of patients on anticancer responses of innate immune cells

• Impact of social/stressed environment on anticancer responses of innate immune cells

• Influence of tumor resistance mechanisms on innate cells

• Cross-talk of the different innate cells among themselves or with adaptive immune cells

Keywords: Cancer, immunotherapy, innate immunity, NK cells, macrophages, dendritic cells, gender, age, social environment

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