Adoptive Immunotherapy With Engineered iNKT Cells to Target Cancer Cells and the Suppressive Microenvironment

Abstract

Invariant Natural Killer T (iNKT) cells are T lymphocytes expressing a conserved semi-invariant TCR specific for lipid antigens (Ags) restricted for the monomorphic MHC class I-related molecule CD1d. iNKT cells infiltrate mouse and human tumors and play an important role in the immune surveillance against solid and hematological malignancies. Because of unique functional features, they are attractive platforms for adoptive cells immunotherapy of cancer compared to conventional T cells. iNKT cells can directly kill CD1d-expressing cancer cells, but also restrict immunosuppressive myelomonocytic populations in the tumor microenvironment (TME) via CD1d-cognate recognition, promoting anti-tumor responses irrespective of the CD1d expression by cancer cells. Moreover, iNKT cells can be adoptively transferred across MHC barriers without risk of alloreaction because CD1d molecules are identical in all individuals, in addition to their ability to suppress graft vs. host disease (GvHD) without impairing the anti-tumor responses. Within this functional framework, iNKT cells are successfully engineered to acquire a second antigen-specificity by expressing recombinant TCRs or Chimeric Antigen Receptor (CAR) specific for tumor-associated antigens, enabling the direct targeting of antigen-expressing cancer cells, while maintaining their CD1d-dependent functions. These new evidences support the exploitation of iNKT cells for donor unrestricted, and possibly off the shelf, adoptive cell therapies enabling the concurrent targeting of cancer cells and suppressive microenvironment.

Target tumor microenvironment by innate T cells

“…Innate T cells, including iNKT, MAIT and γδT cells are unconventional T cell subsets that have the potential to deplete TAMs through powerful NK receptor- and TCR-mediated cytotoxicity ( 27 , 28 , 54 ). These innate-like T cells are activated independently of MHC antigen presentation, and therefore do not recognize mismatch or protein alloantigen to induce GvHD ( 42 , 121 – 123 ).…”

“…The predominant clinical platforms implementing iNKT immunotherapy utilize autologously engrafted PBMC-derived iNKT cells that are activated prior using in vitro glycolipid presentation ( 54 – 56 ). While iNKT-based therapy could be repurposed for TAM depletion, limitations on PBMC iNKT purity and yield demand a novel platform for the generation of iNKT cells.…”

Tumor infiltrating iNKT cells sustain neutrophil pro-tumorigenic functions influencing disease progression in human colorectal cancer

“…iNKT cells are essential components of anti-tumor responses thanks to their well-known cytotoxic properties 16 and active participation in immune surveillance against malignant transformation 10 . However, reduced frequencies and functional impairment of iNKT cells have been associated with poor overall survival in solid or hematological tumors 10 associated with loss of IFNγ secretion and acquisition of an anti-inflammatory phenotype 36 . Nevertheless, αGalCer administration can revert iNKT cells functional impairment 37 as demonstrated in preclinical studies and RCTs 38 .…”

“…Dysbiosis imprints iNKT cells toward a pro-inflammatory phenotype 7 whereas normobiosis restoration upon fecal microbiota transplantation 8,9 and exposure to Short Chain Fatty Acids (SCFA) 8,9 induce their production of regulatory cytokines, such as IL10. Along with the patrolling of tissue integrity, iNKT cells actively participate in the immune surveillance against malignant transformation and tumor progression, including human colorectal cancer (CRC) 10 . CRC is the third most prevalent cancer worldwide and the second leading cause of cancer-related death 11 .…”

“…Because of their fast responsiveness to microbes, iNKT cells can produce a large amount of effector cytokines 1 during the time required for the recruitment, activation and expansion of conventional T cells 13 with the potential to robustly imprint the tumor microenvironment (TME) and the CRC developmental trajectory. iNKT cells are considered important in antitumor immunity 10 and their infiltration in tumoral lesions is a positive prognostic factor in different cancer types 14,15 . Moreover, iNKT cells possess cytotoxic properties 16 and are endowed with cell-killing activities towards different human CRC cell lines and primary patient’s derived cancer epithelial cells through the perforin– granzyme pathway 17 .…”